Heterobicyclic carboxamides as inhibitors for kinases

ABSTRACT

The invention relates to novel organic compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula I and to the use of a compound of formula I for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in the treatment of tumour diseases and ocular neovascular diseases.

The invention relates to bicyclic heterocyclyl compounds substituted atboth rings of formula I and their use in the treatment of the animal orhuman body, to pharmaceutical compositions comprising a compound offormula I and to the use of a compound of formula I for the preparationof pharmaceutical compositions for use in the treatment of proteinkinase dependent diseases, especially of proliferative diseases, such asin particular tumour diseases and ocular neovascularization diseases.

Protein kinases (PKs) are enzymes which catalyze the phosphorylation ofspecific serine, threonine or tyrosine residues in cellular proteins.These post-translational modifications of substrate proteins act asmolecular switch regulating cell proliferation, activation and/ordifferentiation. Aberrant or excessive wild-type or mutated PK activityhas been observed in many disease states including benign and malignantproliferative disorders. In many cases, it has been possible to treatdiseases, such as proliferative disorders, by making use of PKinhibitors.

In view of the large number of protein kinases and the multitude ofproliferative and other PK-related diseases, there is an ever-existingneed to provide compounds that are useful as PK inhibitors and thus inthe treatment of these PK related diseases.

It has now been found that the compounds of formula I show inhibition ofa number of protein kinases. The compounds of formula I, described belowin more detail, especially show inhibition of one or more of thefollowing protein kinases: EphB4, c-Abl, Bcr-Abl, c-Kit, Raf kinasessuch as especially B-Raf, the rearranged during transfection (RET)proto-oncogene, Platelet-derived Growth Factor Receptors (PDGF-Rs), Lck,Hck and most especially the Vascular Endothelial Growth Factor Receptors(VEGF-Rs) such as in particular VEGF-R2. The compounds of formula Ifurther also inhibit mutants of said kinases. In view of theseactivities, the compounds of formula I can be used for the treatment ofdiseases related to especially aberrant or excessive activity of suchtypes of kinases, especially those mentioned.

The invention relates to compounds of the formula I,

or a salt thereof wherein

-   -   R₁ is hydrogen or C₁-C₆alkyl;    -   R₂ is hydrogen or C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ is hydrogen or C₁-C₆alkyl; or    -   R₂ and R₄, taken in combination form a bond;    -   R₅ is hydrogen, C₁-C₆alkyl, or halogen;    -   R₆ represents 0, 1 or 2 residues independently selected at each        occurrence from halogen or C₁-C₆alkyl;    -   R₇ is hydrogen or C₁-C₆alkyl;    -   X is O or S;    -   Z₁ and Z₂ are independently selected from the group consisting        of N and CR₈;    -   R₈ and R₁₀ are independently selected from the group consisting        of hydrogen and C₁-C₆alkyl;    -   R₉ is selected from the group consisting of        (CR₁₁R₁₂)_(n)NR₁₃R₁₄, (CR₁₁R₁₂)_(n)heterocycle,        (CR₁₁R₁₂)_(n)OR₁₅, (CR₁₁R₁₂)_(n)C(O)ER₁₃, and        (CR₁₁R₁₂)_(n)S(O)_(m)R₁₇; or    -   R₈ and R₉, taken in combination, together with the atoms to        which they are attached, form a saturated 4-7 membered        heterocyclic ring having 1 or 2 ring heteroatoms selected from        N, O or S, which heterocyclic ring is substituted with 0, 1, or        2 residues independently selected from the group consisting of        oxo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy,        halogen, hydroxyl, amino, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl,        mono- and di-C₁-C₆alkylaminoC₁-C₆alkyl,        C₃-C₇cycloalkylC₁-C₄alkyl, heterocycleC₁-C₄alkyl, C₁-C₆alkanoyl,        mono- and di-C₁-C₆alkylamino, aminocarbonyl, mono- and        di-C₁-C₆alkylaminocarbonyl, mono- and        di-C₁-C₄alkylaminoC₁-C₄alkanoyl, C₁-C₆alkoxycarbonyl,        C₁-C₆alkylsulfonyl, aminosulfonyl, and mono- and        di-C₁-C₆alkylaminosulfonyl;    -   Ar₂ is selected from the group consisting of phenyl, naphthyl, a        monocyclic or bicyclic heteroaryl, and bicyclic or tricyclic        heterocycle wherein each heteroaryl or heterocycle residue has        1, 2, 3 or 4 ring heteroatoms selected from N, O or S and        wherein the phenyl, naphthyl, heteroaryl or heterocycle group is        unsubstituted or substituted by 1, 2, or 3 groups independently        selected from C₁-C₈alkyl, C₁-C₈haloalkyl, hydroxyC₁-C₆alkyl,        C₁-C₈alkoxy, C₁-C₈haloalkoxy, halogen, hydroxy, amino,        aminoC₁-C₆alkyl, mono- and di-C₁-C₆alkylaminoC₁-C₆alkyl, mono-        and di-C₁-C₆alkylamino, CO₂C₁-C₆alkyl, phenylC₀-C₄alkyl,        C₃-C₇cycloalkylC₀-C₄alkyl, spirocyclic C₃-C₇cycloalkyl,        aminosulfonyl, and mono- and di-C₁-C₆alkylaminosulfonyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   E is absent, O or NR₁₈;    -   R₁₁, R₁₂ and R₁₈ are the same or different and are independently        selected at each occurrence from the group consisting of        hydrogen and C₁-C₄alkyl; and    -   R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are independently selected at each        occurrence from the group consisting of hydrogen, C₁-C₆alkyl,        C₁-C₆alkanoyl, C₃-C₆cycloalkyl, phenyl and heterocycle, each of        which is substituted with 0, 1 or 2 residues independently        selected from C₁-C₄alkyl, C₁-C₄alkoxy, halogen, hydroxyl, amino,        and mono- and di-C₁-C₆alkylamino.

The present invention also relates to a method of treating a kinasedependent and/or proliferative disease comprising administering acompound of the formula I to a warm-blooded animal, especially a human,and the use of a compound of the formula I, especially for treating akinase dependent disease or disorder. The present invention also relatesto pharmaceutical preparations comprising a compound of the formula I,especially for the treatment of a kinase dependent disease or disorder,a process for the manufacture of a compound of the formula I, and novelstarting materials and intermediates for their manufacture. The presentinvention also relates to the use of a compound of formula I in themanufacture of a pharmaceutical preparation for the treatment of akinase dependent disease.

The general terms used hereinbefore and hereinafter preferably have,within this disclosure, the following meanings, unless otherwiseindicated (where preferred embodiments can be defined by replacing oneor more up to all general expressions or symbols with (a) more specificor more preferred definition(s) given herein):

Certain compounds of Formula I provided herein are compounds accordingto Formula II:

-   -   or a salt thereof wherein    -   R₁ is hydrogen or C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₅ is hydrogen or halogen;    -   R₇ is hydrogen or C₁-C₆alkyl;    -   X is O or S;    -   R₈ is selected from the group consisting of hydrogen and        C₁-C₄alkyl;    -   R₉ is selected from the group consisting of        (CR₁₁R₁₂)_(n)NR₁₃R₁₄, (CR₁₁R₂₂)_(n)heterocycle,        (CR₁₁R₂₂)_(n)OR₁₅, (CR₁₁R₂₂)_(n)C(O)ER₁₃, and        (CR₁₁R₁₂)_(n)S(O)_(m)R₁₇; or    -   R₈ and R₉, taken in combination with the atoms to which they are        attached form a saturated 4-7 membered heterocyclic ring having        1 or 2 ring heteroatoms selected from N, O or S, which        heterocyclic ring is substituted with 0, 1, or 2 residues        independently selected from the group consisting of C₁-C₆alkyl,        C₁-C₆haloalkyl, halogen, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl,        C₃-C₇cycloalkylC₁-C₄alkyl, heterocycleC₁-C₄alkyl, C₁-C₆alkanoyl,        mono- and di-C₁-C₆alkylaminocarbonyl, mono- and        di-C₁-C₄alkylaminoC₁-C₄alkanoyl, C₁-C₆alkoxycarbonyl, and        C₁-C₆alkylsulfonyl.    -   Ar₂ is phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryl,        wherein each heteroaryl has 1, 2, or 3 ring heteroatoms selected        from N, O or S and wherein the phenyl, naphthyl, or heteroaryl        group is unsubstituted or substituted by 1, 2, or 3 groups        independently selected from the group consisting of C₁-C₆alkyl,        C₁-C₆haloalkyl, halo, hydroxyl, CO₂R, phenyl, and        C₃-C₇cycloalkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   E is O or NR₁₈;    -   R₁₁, R₁₂ and R₁₈ are the same or different and are independently        selected at each occurrence from the group consisting of        hydrogen and C₁-C₄alkyl; and    -   R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are independently selected at each        occurrence from the group consisting of hydrogen, C₁-C₆alkyl,        C₃-C₆cycloalkyl, phenyl and heterocycle, each of which is        substituted with 0, 1 or 2 residues independently selected from        hydroxyl, amino, and mono- and di-C₁-C₆alkylamino.

Certain other compounds of Formula I provided herein are compoundsaccording to Formula III:

-   -   or a salt thereof wherein    -   R₁ is hydrogen or C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₅ is hydrogen or halogen;    -   R₇ is hydrogen or C₁-C₆alkyl;    -   X is O or S;    -   R₈ is selected from the group consisting of hydrogen and        C₁-C₄alkyl;    -   R₉ is selected from the group consisting of        (CR₁₁R₁₂)_(n)NR₁₃R₁₄, (CR₁₁R₁₂)_(n)heterocycle,        (CR₁₁R₁₂)_(n)OR₁₅, (CR₁₁R₁₂)_(n)C(O)ER₁₃, and        (CR₁₁R₁₂)_(n)S(O)_(m)R₁₇; or    -   R₈ and R₉, taken in combination together with the atoms to which        they are attached form a saturated 4-7 membered heterocyclic        ring having 1 or 2 ring heteroatoms selected from N, O or S,        which heterocyclic ring is substituted with 0, 1, or 2 residues        independently selected from the group consisting of C₁-C₆alkyl,        C₁-C₆haloalkyl, halogen, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl,        C₃-C₇cycloalkylC₁-C₄alkyl, heterocycleC₁-C₄alkyl, C₁-C₆alkanoyl,        mono- and di-C₁-C₆alkylaminocarbonyl, mono- and        di-C₁-C₄alkylaminoC₁-C₄alkanoyl, C₁-C₆alkoxycarbonyl, and        C₁-C₆alkylsulfonyl.    -   Ar₂ is phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryl,        wherein each heteroaryl has 1, 2, or 3 ring heteroatoms selected        from N, O or S and wherein the phenyl, naphthyl, or heteroaryl        group is unsubstituted or substituted by 1, 2, or 3 groups        independently selected from the group consisting of C₁-C₆alkyl,        C₁-C₆haloalkyl, halo, hydroxyl, CO₂R, phenyl, and        C₃-C₇cycloalkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   E is O or NR₁₈;    -   R₁₁, R₁₂ and R₁₈ are the same or different and are independently        selected at each occurrence from the group consisting of        hydrogen and C₁-C₄alkyl; and    -   R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are independently selected at each        occurrence from the group consisting of hydrogen, C₁-C₆alkyl,        C₃-C₆cycloalkyl, phenyl and heterocycle, each of which is        substituted with 0, 1 or 2 residues independently selected from        hydroxyl, amino, and mono- and di-C₁-C₆alkylamino.

In certain embodiments, compounds of formula I, II, and/or III includethose compounds in which R₁ and R₃ are hydrogen. In certain othercompounds of formula I, II, and/or III, R₁ is hydrogen or C₄-C₄alkyl(e.g., methyl or ethyl), R₃ is hydrogen and either (1) R₂ and R₄ arehydrogen or (2) R₂ and R₄, taken in combination form a bond.

In certain embodiments R₅ is selected from hydrogen, methyl, methoxy,fluoro, or chloro. In certain other embodiments R₅ is selected fromhydrogen or fluoro. In certain compounds of formula I, R₁ is methyl orethyl and R₅ is fluoro.

In certain other embodiments, R₆ is absent.

In certain compounds of Formula I, II, or III, R₇ is hydrogen or methyl.In yet other embodiments, R₇ is hydrogen.

In yet other embodiments, X is oxygen.

Certain compounds of formula I, II, and/or III include those in which R₁is hydrogen or C₁-C₄alkyl (e.g., methyl or ethyl), R₃ is hydrogen, R₅ ishydrogen or fluoro, R₆ is absent, X is oxygen and either (1) R₂ and R₄are hydrogen or (2) R₂ and R₄, taken in combination form a bond.

In certain embodiments, R₈ is hydrogen. In other embodiments R₁₀ ishydrogen. In yet other embodiments, R₈ and R₁₀ are hydrogen.

In certain embodiments, R₁₀ is hydrogen and R₈ and R₉, taken incombination, form a saturated 5 or 6 membered heterocyclic ring having 1ring nitrogen atoms, which heterocyclic ring is substituted with 0, 1,or 2 residues independently selected from the group consisting ofC₁-C₄alkyl, C₁-C₄haloalkyl, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,heterocycleC₁-C₄alkyl, C₁-C₄alkanoyl, mono- and di-C_(r)C₄alkylaminocarbonyl, mono- and di-C₁-C₄alkylaminoC₁-C₄alkanoyl, mono-and di-C₁-C₄alkylaminocarbonylC₁-C₄alkyl, aminocarbonylC₁-C₄alkyl,C₁-C₄alkoxycarbonyl, and C₁-C₄alkylsulfonyl.

Certain compounds of Formula I, II, or III, in which R₈ and R₉ form aring include those in which the fragment:

is selected from a residue of the formula:

and salts thereof, whereinp is 0 or 1;R₁₉, R_(19a), R₂₀, R₂₁, R_(21a), R₂₃, and R₂₃, are independentlyselected from the group consisting of hydrogen, oxo, hydroxyl,C₁-C₄alkyl, C₁-C₄haloalkyl, hydroxyC₁-C₄alkyl, HOC(O)CH₂, NH₂C(O)CH₂,mono- and di-C₁-C₄alkylNHMeC(O)CH₂, C₁-C₄alkanoyl, mono- anddi-C₁-C₄alkylC₁-C₄alkanoyl, C₁-C₄sulfonyl, or R₁₉ and R_(19a) taken incombination or R₂₁ and R_(21a) taken in combination or R₂₃ and R_(23a)taken in combination form a three to seven membered spiro cyclic ring.In certain other compounds, R_(19a), R_(21a), R₂₃, and R_(23a), arehydrogen, two of variables R₁₉, R₂₀ or R₂₁ are hydrogen and other isselected from the group consisting of hydrogen, methyl, ethyl, orhydroxyethyl.

Certain embodiments provide compounds of Formula I or III represented bythe Formula IV:

and salts thereof, whereinp is 0 or 1;R₁₉, R₂₀, and R₂₁ are independently selected from the group consistingof hydrogen, C₁-C₄alkyl, hydroxyC₁-C₄alkyl, NH₂C(O)CH₂, and NHMeC(O)CH₂.

Certain compounds of Formula IV include those compounds in which two ofvariables R₁₉, R₂₀ or R₂₁ are hydrogen and other is selected from thegroup consisting of hydrogen, methyl, ethyl, or hydroxyethyl. Certainother compounds of formula IV include those in which p is 0, R₁₉ and R₂₁are hydrogen and R₂₀ is selected from hydrogen, methyl, and ethyl.

Certain embodiments provide compounds of Formula I or III represented bythe Formula V:

and salts thereof, wherein

-   -   R₉ is selected from the group consisting of CH₂NR₁₃R₁₄, CH₂OR₁₅,        CH₂C(O)ER₁₃, and CH₂S(O)₂ER₁₇; or    -   E is absent, O or NR₁₈;    -   R₁₈ is hydrogen, methyl or ethyl; and    -   R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are independently selected at each        occurrence from the group consisting of hydrogen, C₁-C₄alkyl,        and hydroxyC₁-C₄alkyl.

In certain compounds of Formula I, II, III, or V, R₉ is selected fromthe group consisting of (CH₂)_(n)NHR₁₃, (CR₁₁R₁₂)_(n)heterocycle,(CR₁₁R₁₂)_(n)OR₁₅, (CH₂)_(n)S(O)_(m)R₁₇ and (CH₂)_(n)S(O)_(m)N(R₁₈)₂;

-   -   n is 1 or 2;    -   R₁₃ is hydrogen, C₁-C₄alkyl, hydroxyC₁-C₄alkyl, or        C₃-C₆cycloalkyl;    -   R₁₅ is hydrogen or C₁-C₄alkyl;    -   R₁₇ is C₁-C₄alkyl;    -   R₁₈ is independently selected at each occurrence from the group        consisting of hydrogen, methyl or ethyl.

In certain other compounds of Formula I or III, or a salt thereof,wherein

-   -   R₁ is hydrogen, methyl or ethyl;    -   R₃ is hydrogen;    -   R₅ is hydrogen, fluoro or chloro;    -   X is O or S;    -   R₈ is selected from the group consisting of hydrogen and        C₁-C₄alkyl;    -   R₉ is selected from the group consisting of CH₂NR₁₃R₁₄,        CH₂heterocycle, CH₂OR₁₅, CH₂C(O)ER₁₃, and CH₂S(O)₂ER₁₇; or    -   R₈ and R₉, taken in combination form a saturated 4-7 membered        heterocyclic ring having one ring nitrogen atom, which        heterocyclic ring is substituted with 0, 1, or 2 residues        independently selected from the group consisting of C₁-C₆alkyl,        C₁-C₆haloalkyl, halogen, C₁-C₆alkanoyl, and C₁-C₆alkylsulfonyl;    -   Ar₂ is phenyl, 5 membered monocyclic heteroaryl, wherein each        heteroaryl has one ring nitrogen and 0 or 1 additional ring        heteroatoms selected from N, O or S and wherein the phenyl or        heteroaryl group is unsubstituted or substituted by 1, 2, or 3        groups independently selected from the group consisting of        C₁-C₆alkyl, C₁-C₆haloalkyl, halo, hydroxyl, CO₂R, phenyl, and        C₃-C₇cycloalkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   E is O or NR₁₈;    -   R₁₈ is selected from the group consisting of hydrogen and        C₁-C₄alkyl; and    -   R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are independently selected at each        occurrence from the group consisting of hydrogen, C₁-C₆alkyl,        C₃-C₆cycloalkyl, phenyl and heterocycle, each of which is        substituted with 0, 1 or 2 residues independently selected from        hydroxyl, amino, and mono- and di-C₁-C₆alkylamino.

In certain compounds of Formula I, II, III, IV, or V, or salts thereof,Ar₂ is phenyl which is unsubstituted or substituted with 1 or 2 groupsindependently selected from halogen, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄haloalkyl, and C₁-C₄haloalkoxy. In other compounds of Formula I,II, III, IV, or V, or salts thereof, Ar₂ is a five membered heteroarylhaving 1 ring nitrogen atom and 0 or 1 additional ring heteroatomsselected from N and O and wherein said heteroaryl group is unsubstitutedor substituted with 1 or 2 groups independently selected from the groupconsisting of C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy,halogen, amino, aminoC₁-C₄alkyl, mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl,mono- and di-C₁-C₄alkylamino, hydroxyl, CO₂C₁-C₄alkyl, phenylC₀-C₄alkyl,C₃-C₆cycloalkylC₀-C₂alkyl, aminosulfonyl, and mono- anddi-C₁-C₄alkylaminosulfonyl. In certain other compounds of Formula I, II,III, IV, or V, or salts thereof, Ar₂ is a bicyclic heterocycle having aring nitrogen atom and 0 or 1 additional ring heteroatoms selected fromN and O which is saturated, partially unsaturated, or partially aromatic(e.g., a heteroaryl or phenyl ring fused to a heterocyclic orcarbocyclic ring such that the bicyclic heterocycle comprises at leastone ring heteroatom in at least one ring) and wherein the bicyclicheterocycle is unsubstituted or substituted by 1 or 2 groupsindependently selected from the group consisting of C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, halogen, amino,aminoC₁-C₄alkyl, mono- and di-C₄-C₄alkylaminoC₁-C₄alkyl, mono- anddi-C₁-C₄alkylamino, hydroxyl, CO₂C₁-C₄alkyl, phenylC₀-C₄alkyl,C₃-C₆cycloalkylC₀-C₂alkyl, aminosulfonyl, and mono- anddi-C₁-C₄alkylaminosulfonyl. In certain compounds in which Ar₂ is a fivemembered heteroaryl or a bicyclic heterocycle, Ar₂ is unsubstituted orsubstituted with a C₁-C₄alkyl or a hydroxyC₁-C₄alkyl.

In certain compounds of Formula I, II, III, IV, or V, or salts thereof,Ar₂ is a group of the formula:

-   -   wherein    -   R₂₂ is selected from C₁-C₄alkyl, C₃-C₆cycloalkyl,        C₃-C₆cycloalkylC₁-C₄alkyl, C₁-C₄haloalkyl, hydroxyC₁-C₄alkyl,        phenyl, 5 and 6 membered heterocycle; and Z is O, NH or        N(C₁-C₄alkyl). In certain compounds R₂₂ is selected from        C₁-C₄alkyl, C₃-C₆cycloalkyl, 1-methyl-C₃-C₆cycloalkyl,        C₁₋₂haloalkyl, and hydroxyC₁-C₄alkyl; and Z is O or NH. In still        other compounds R₂₂ is selected from isopropyl, tert-butyl,        cyclopropyl, cyclobutyl, 1-methyl-cyclopropyl,        1-trifluoromethyl-cyclopropyl, 1-ethyl-cyclopropyl,        1-methylcyclobutyl, 1-methylcyclobutyl, hydroxyl-tert-butyl, and        trifluoromethyl; and Z is O. In certain compound where Z is N,        the compounds may exist as one or both of the 1H or 2H pyrazole        tautomer, e.g.,

Certain compounds of Formula I include the exemplified compoundsprepared herein. Certain compounds of Formula I include compoundsselected from the group consisting of:

-   5-(7-Ethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (4-fluoro-3-trifluoromethyl-phenyl)-amide;-   6-Tetrazol-2-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (4-fluoro-3-trifluoromethyl-phenyl)-amide;-   5-(6-Cyclopropylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic    acid (4-fluoro-3-trifluoromethyl-phenyl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   N-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(6-(methylsulfonylmethyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide;-   N-(4-Methoxy-3-(trifluoromethyl)phenyl)-5-(6-(methylamino)methyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide;-   5-(7-Methanesulfonyl-5,6,7,8-tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   5-[6-(2-Hydroxy-ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl phenyl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (4-fluoro-3-trifluoromethyl-phenyl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   (−)-(S)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   (+)-(R)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   4-Fluoro-5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (5-tert-butyl-2H-pyrazol-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (2-fluoro-3-trifluoromethyl-phenyl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-isobutyl-isoxazol-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-2H-pyrazol-3-yl)-amide;-   5-(6-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-fluoro-5-trifluoromethyl-phenyl)-amide;-   6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-tert-butyl-isoxazol-5-yl)-amide;-   (−)-5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   (+)-5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   4-Fluoro-2-methyl-5-(6-((methylamino)methyl)pyrimidin-4-yloxy)-N-(3(trifluoromethyl)-phenyl)-1H-indole-1-carboxamide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   4-Fluoro-5-(6-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-trifluoromethyl-1H-pyrazol-3-yl)-amide;-   (+)-5-((S)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   (−)-5-((R)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4    d]pyrimidin-4-yloxy)-indole-1-carboxylic acid    [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   5-(2-(2-Morpholinoethyl)pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-isopropyl-isoxazol-3-yl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-[6-((1R,4S)-5-Acetyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6-Methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic    acid (2-fluoro-3-trifluoromethyl-phenyl)-amide;-   5-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-pyridin-4-yloxy]-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-[7-(3-Diethylamino-propionyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(2-Cyclopropylcarbamoyl-pyridin-4-yloxy)-indole-1-carboxylic acid    (3-trifluoromethyl-phenyl)-amide;-   6-(5-Methyl-tetrazol-2-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic    acid (4-fluoro-3-trifluoromethyl-phenyl)-amide;-   5-((S)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   5-((R)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(4-fluoro-phenyl)-isoxazol-3-yl]-amide;-   5-[6-(4-Methanesulfonylamino-piperidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-[7-(2-Hydroxy-ethyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(2-Methylcarbamoyl-pyridin-4-yloxy)-indole-1-carboxylic acid    (3-trifluoromethyl-phenyl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(2-hydroxy-1,1-dimethyl-ethyl)-2H-pyrazol-3-yl]-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-trifluoromethyl-pyridin-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (1-methyl-1H-indol-4-yl)-amide;-   5-(6-Morpholin-4-ylmethyl-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide hydrochloride;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   5-(2-Hydroxymethyl-pyridin-4-yloxy)-indole-1-carboxylic acid    (3-trifluoromethylphenyl)-amide;-   5-(6-Isobutyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (3-trifluoromethyl-phenyl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-phenyl-2H-pyrazol-3-yl)-amide;-   2-Methyl-5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   4-Fluoro-5-((S)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   4-Fluoro-5-((R)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   5-(6-Pyrrolidin-1-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(2-Cyclopropylaminomethyl-pyridin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   (−)-5-((S)-7-Acetyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   4-Fluoro-5-(2-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-amide; and    a tautomer thereof and/or a pharmaceutically acceptable salt    thereof.

In a preferred embodiment the present invention relates to a compoundselected from the group consisting of

-   5-(7-Ethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (4-fluoro-3-trifluoromethyl-phenyl)-amide;-   6-Tetrazol-2-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (4-fluoro-3-trifluoromethyl-phenyl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   N-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(6-(methylsulfonylmethyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide;-   5-(7-Methanesulfonyl-5,6,7,8-tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   5-[6-(2-Hydroxy-ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl phenyl)-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   (−)-(S)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   (+)-(R)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   4-Fluoro-5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (2-fluoro-3-trifluoromethyl-phenyl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide;-   5-(5,6,7,8-Tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   (+)-5-((S)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-tert-butyl-isoxazol-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-isopropyl-isoxazol-3-yl)-amide;-   5-[7-(3-Diethylamino-propionyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   5-((S)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   5-((R)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide;-   5-((S)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (5-isopropyl-1H-pyrazol-3-yl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (5-cyclopropyl-1H-pyrazol-3-yl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    [5-(1-methyl cyclopropyl)-isoxazol-3-yl]-amide;-   5-((S)-7-Acetyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1 trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide;-   5-[(S)-6-Methyl-7-(3-methyl-butyryl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylic    acid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]amide;-   5-((S)-7-Cyclopropylmethyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]amide;-   5-((S)-7-Ethyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide;-   5-((S)-7-Cyclopropanecarbonyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-((S)-6,7-Dimethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-((S)-7-Ethyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-amide;-   (−)-5-((S)-7-Acetyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   4-Methyl-5-((S)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-((S)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide;-   5-((S)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (1-tert-butyl-1H-pyrazol-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-4-methyl-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [5-(1 trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide;-   5-(6,7,8,9-Tetrahydro-5H-pyrimido[4,5-c]azepin-4-yloxy)-indole-1-carboxylic    acid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide;-   5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid [4-methyl-5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide;-   5-((S)-7-Acetyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-4-methyl-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   4-Methyl-5-((S)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (1-tert-butyl-1H-pyrazol-3-yl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-amide;-   5-((S)-7-Acetyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (1-tert-butyl-1H-pyrazol-3-yl)-amide;-   5-((S)-7-Butyryl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   5-((S)-6-Methyl-7-propionyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid (5-cyclopropyl-isoxazol-3-yl)-amide;-   4-[1-(5-Cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-6-carboxylic    acid methylamide;-   N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-(2-((methylamino)methyl)pyridin-4-yloxy)-1H-indole-1-carboxamide;-   5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid    (1,5-dicyclopropyl-1H-pyrazol-3-yl)-amide;-   5-(6-Methylaminomethyl-pyrimidin-4 yloxy)-indole-1-carboxylic acid    (5-cyclopropyl-1-ethyl-1H-pyrazol-3-yl)-amide;-   4-Methyl-5-((S)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic    acid-   (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-amide; and tautomer    thereof and/or a pharmaceutically acceptable salt thereof.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl and the like.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, that is substituted by one or more halo groups as definedherein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl orpolyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo,bromo, chloro or fluoro within the alkyl group. Dihaloalky andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. Preferably, thepolyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2halo groups. Non-limiting examples of haloalkyl include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refersto an alkyl having all hydrogen atoms replaced with halo atoms.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-20 carbon atoms in the ring portion. Preferably, thearyl is a (C₆-C₁₀) aryl. Non-limiting examples include phenyl, biphenyl,naphthyl or tetrahydronaphthyl, each of which may optionally besubstituted by 1-4 substituents, such as alkyl, trifluoromethyl,cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)—O—, aryl-O—,heteroaryl-O—, amino, thiol, alkyl-S—, aryl-S—, nitro, cyano, carboxy,alkyl-O—C(O)—, carbamoyl, alkyl-S(O)—, sulfonyl, sulfonamido,heterocyclyl and the like.

Furthermore, the term “aryl” as used herein, refers to an aromaticsubstituent which can be a single aromatic ring, or multiple aromaticrings that are fused together, linked covalently, or linked to a commongroup such as a methylene or ethylene moiety. The common linking groupalso can be a carbonyl as in benzophenone or oxygen as in diphenyletheror nitrogen as in diphenylamine.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Preferably, alkoxy groups have about 1-7, more preferablyabout 1-4 carbons.

As used herein, the term “alkanoyl” refers to a group R—C(O)— of from 1to 10 carbon atoms of a straight, branched, or cyclic configuration or acombination thereof, attached to the parent structure through carbonylfunctionality. R in the alkanoyl residue is hydrogen, alkyl, cycloalkyl,or cycloalkyl-alkyl.

As used herein, the term “carbamoyl” refers to H₂NC(O)—, alkyl-NHC(O)—,(alkyl)₂NC(O)—, aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aryl-alkyl-NHC(O)—, andalkyl(aryl-alkyl)-NC(O)—.

As used herein, the term “sulfonyl” refers to R—SO₂—, wherein R ishydrogen, alkyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, alkoxy,aryloxy, cycloalkyl, or heterocyclyl.

As used herein, the term “sulfonamido” refers to alkyl-S(O)₂—NH—,aryl-S(O)₂—NH—, aryl-alkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—,heteroaryl-alkyl-S(O)₂—NH—, alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-,aryl-alkyl-S(O)₂—N(alkyl)-, heteroaryl-S(O)₂—N(alkyl)-, andheteroaryl-alkyl-S(O)₂—N(alkyl)-.

As used herein, the term “heterocyclyl” or “heterocyclo” refers to anoptionally substituted, saturated or unsaturated non-aromatic ring orring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-,8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or15-membered tricyclic ring system and contains at least one heteroatomselected from O, S and N, where the N and S can also optionally beoxidized to various oxidation states. The heterocyclic group can beattached at a heteroatom or a carbon atom. The heterocyclyl can includefused or bridged rings as well as spirocyclic rings. Examples ofheterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane,morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane, and thiomorpholine.

The term “heterocyclyl” further refers to heterocyclic groups as definedherein substituted with 1, 2 or 3 substituents selected from the groupsconsisting of the following:

-   -   (a) alkyl;    -   (b) hydroxy (or protected hydroxy);    -   (c) halo;    -   (d) oxo, i.e., ═O;    -   (e) amino, alkylamino or dialkylamino;    -   (f) alkoxy;    -   (g) cycloalkyl;    -   (h) carboxyl;    -   (i) heterocyclooxy, wherein heterocyclooxy denotes a        heterocyclic group bonded through an oxygen bridge;    -   (j) alkyl-O—C(O)—;    -   (k) mercapto;    -   (l) nitro;    -   (m) cyano;    -   (n) sulfamoyl or sulfonamido;    -   (o) aryl;    -   (p) alkyl-C(O)—O—;    -   (q) aryl-C(O)—O—;    -   (r) aryl-S—;    -   (s) aryloxy;    -   (t) alkyl-S—;        formyl, i.e., HC(O)—;        carbamoyl;    -   (w) aryl-alkyl—; and    -   (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy,        amino, alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

As used herein, the term “cycloalkyl” refers to saturated or unsaturatedmonocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbonatoms, preferably 3-9, or 3-7 carbon atoms, each of which can beoptionally substituted by one, or two, or three, or more substituents,such as alkyl, halo, oxo, hydroxy, alkoxy, alkyl-C(O)—, acylamino,carbamoyl, alkyl-NH—, (alkyl)₂N—, thiol, alkyl-S—, nitro, cyano,carboxy, alkyl-O—C(O)—, sulfonyl, sulfonamido, sulfamoyl, andheterocyclyl. Exemplary monocyclic hydrocarbon groups include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl and cyclohexenyl. Exemplary bicyclic hydrocarbon groupsinclude bornyl, indyl, hexahydroindyl, tetrahydronaphthyl,decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl,2,6,6-trimethylbicyclo[3.1.1]heptyl, and bicyclo[2.2.2]octyl. Exemplarytricyclic hydrocarbon groups include adamantyl.

As used herein, the term “sulfamoyl” refers to H₂NS(O)₂—,alkyl-NHS(O)₂—, (alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—,(aryl)₂NS(O)₂—, heteroaryl-NHS(O)₂—, (aryl-alkyl)-NHS(O)₂—, and(heteroaryl-alkyl)-NHS(O)₂—.

As used herein, the term “aryloxy” refers to both an —O-aryl and an—O-heteroaryl group, wherein aryl and heteroaryl are defined herein.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or polycyclic-aromatic ring system, having 1 to8 heteroatoms selected from N, O or S. Preferably, the heteroaryl is a5-10 or 5-7 membered ring system. Typical heteroaryl groups include 2-or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl,3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-,4-, or 5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloaliphatic, or heterocyclylrings, where the radical or point of attachment is on the heteroaromaticring. Nonlimiting examples include but are not limited to 1-, 2-, 3-,5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-,3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-,4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-,6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-,3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl,3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, or 8-4-aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-,7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-,2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-,6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-,3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl,2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

A heteroaryl group may be mono-, bi-, i-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat may be defined, in terms of absolute stereochemistry, as (R)- or(S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto. Pharmaceuticallyacceptable acid addition salts can be formed with inorganic acids andorganic acids, e.g., acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts. Inorganicacids from which salts can be derived include, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, and aluminum;particularly preferred are the ammonium, potassium, sodium, calcium andmagnesium salts. Organic bases from which salts can be derived include,for example, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchange resins, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. The pharmaceutically acceptable salts of the presentinvention can be synthesized from a parent compound, a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting free acid forms of these compounds with astoichiometric amount of the appropriate base (such as Na, Ca, Mg, or Khydroxide, carbonate, bicarbonate, or the like), or by reacting freebase forms of these compounds with a stoichiometric amount of theappropriate acid. Such reactions are typically carried out in water orin an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred, where practicable. Lists of additionalsuitable salts can be found, e.g., in “Remington's PharmaceuticalSciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); andin “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” byStahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of the invention, i.e. compounds offormula (I), wherein (1) one or more atoms are replaced by atoms havingthe same atomic number, but an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature, and/or (2) theisotopic ratio of one or more atoms is different from the naturallyoccurring ratio.

Examples of isotopes suitable for inclusion in the compounds of theinvention comprises isotopes of hydrogen, such as ²H and ³H, carbon,such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labeled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. Incertain compounds of Formula I, residues R₉ or the ring formed by thecombination of R₈ and R₉ may comprise one or more deuterium atoms toimprove metabolic stability of the compound in vivo.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula I that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula I by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula I with the co-crystal former under crystallization conditionsand isolating co-crystals thereby formed. Suitable co-crystal formersinclude those described in WO 2004/078163. Hence the invention furtherprovides co-crystals comprising a compound of formula I.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329). Except insofar as any conventional carrier is incompatiblewith the active ingredient, its use in the therapeutic or pharmaceuticalcompositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by VEGF or a receptor thereof, or (ii) associatedwith VEGF activity or the activity of a VEGF receptor, or (iii)characterized by abnormal activity of VEGF or a receptor thereof; or (2)reducing or inhibiting the activity of VEGF or a receptor thereof; or(3) reducing or inhibiting the expression of VEGF or a receptor thereof.In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially reducing or inhibiting the activity of VEGF or a receptorthereof; or at least partially reducing or inhibiting the expression ofVEGF or a receptor thereof. The meaning of the term “a therapeuticallyeffective amount” as illustrated in the above embodiment for VEGF or areceptor thereof applies by the same means to any other relevantproteins/peptides/enzymes, such as Ret, PDGFR alpha, and ckit.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In a preferred embodiment, the subjectis a human.

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., slowing or arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In anotherembodiment “treating” or “treatment” refers to alleviating orameliorating at least one physical parameter including those which maynot be discernible by the patient. In yet another embodiment, “treating”or “treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers topreventing or delaying the onset or development or progression of thedisease or disorder.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50 enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds, which are inactive or have low activity comparedto the corresponding active drug compound, that contain one or moreprotective groups and are converted to an active form by metabolism orsolvolysis. Both the active drug form and any released metabolicproducts should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof (a) hydroxyl groups with lipophilic carboxylic acids (e.g., acarboxylic acid having at least one lipophilic moiety), or (b)carboxylic acid groups with lipophilic alcohols (e.g., an alcohol havingat least one lipophilic moiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acylderivatives of thiols and O-acyl derivatives of alcohols or phenols,wherein acyl has a meaning as defined herein. Preferred arepharmaceutically acceptable ester derivatives convertible by solvolysisunder physiological conditions to the parent carboxylic acid, e.g.,lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzylesters, mono- or di-substituted lower alkyl esters, such as the□-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart. In addition, amines have been masked as arylcarbonyloxymethylsubstituted derivatives which are cleaved by esterases in vivo releasingthe free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).Moreover, drugs containing an acidic NH group, such as imidazole, imide,indole and the like, have been masked with N-acyloxymethyl groups(Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups havebeen masked as esters and ethers. EP 039,051 (Sloan and Little)discloses Mannich-base hydroxamic acid prodrugs, their preparation anduse.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and acarrier, e.g., a pharmaceutically acceptable carrier. The pharmaceuticalcomposition can be formulated for particular routes of administrationsuch as oral administration, ophthalmic administration (e.g., topicaladministration, intravitreal injection, implant (including intravitreal,transscleral, sub-Tenon, and the like, depot or the like), andparenteral administration, etc. In addition, the pharmaceuticalcompositions of the present invention can be made up in a solid formincluding capsules, tablets, pills, granules, powders or suppositories,or in a liquid form including solutions, suspensions or emulsions. Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifers and buffers etc.

Typically, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Certain injectable compisitions include ocular implants and ocular depotformulations which are suitable for intraocular, periocular,subconjunctival and/or sub-tenon administration. Typicaly injectablecompositions comprise a compound of formula (I) in combination with abiocompatible or biodegradable polymeric material.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Carriers includeabsorbable pharmacologically acceptable solvents to assist passagethrough the skin of the host. For example, transdermal devices are inthe form of a bandage comprising a backing member, a reservoircontaining the compound optionally with carriers, optionally a ratecontrolling barrier to deliver the compound of the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for ocularapplication, e.g., for the treatment of ocular disease, e.g., forprophylactic or therapeutic use in the treatment of maculardegeneration, diabetic retinopathy, rubeosis iridis, neovascularizationof the cornea, sclera, retina or other ocular tissue and the like. Theyare thus particularly suited for use in topical formulations well-knownin the art. Such may contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

Certain suitable topical eye drop formulations comprise an aqueoussolution or aqueous suspension of a compound of Formula I, optionallyfurther comprising one or more preservatives, tonicity agents, and/orlubricants.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They are conveniently delivered in theform of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are preferably packagedusing materials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds of formula I in free form or in pharmaceuticallyacceptable salt form, exhibit valuable pharmacological properties, e.g.VEGF receptor modulating properties, e.g. as indicated in in vitro andin vivo tests as provided in the next sections and are thereforeindicated for therapy.

Based on the property of the compounds of formula I as potent VEGFreceptor inhibitors, the compounds of formula I are especially suitablefor the treatment of diseases associated with deregulated angiogenesis,especially diseases caused by ocular neovascularisation, especiallyretinopathies such as diabetic retinopathy or age-related maculardegeneration, rubeosis iridis, psoriasis, Von Hippel Lindau disease,hemangioblastoma, angioma, mesangial cell proliferative disorders suchas chronic or acute renal diseases, e.g. diabetic nephropathy, malignantnephrosclerosis, thrombotic microangiopathy syndromes or transplantrejection, or especially inflammatory renal disease, such asglomerulonephritis, especially mesangioproliferative glomerulonephritis,haemolytic-uraemic syndrome, diabetic nephropathy, hypertensivenephrosclerosis, atheroma, arterial restenosis, autoimmune diseases,acute inflammation, fibrotic disorders (e.g. hepatic cirrhosis),diabetes, endometriosis, chronic asthma, arterial orpost-transplantational atherosclerosis, neurodegenerative disorders, andespecially neoplastic diseases (especially solid tumours but alsoleukemias), such as especially breast cancer, adenocarcinoma, colorectalcancer, lung cancer (especially non-small-cell lung cancer), renalcancer, liver cancer, pancreatic cancer, ovarian cancer or cancer of theprostate as well as myeloma, especially multiple myeloma,myelodysplastic syndrome, AML (acute myeloid leukemia), AMM (agnogenicmyeloid metaplasia), mesothelioma, glioma and glioblastoma. A compoundof formula I is especially suited also to preventing the metastaticspread of tumours and the growth of micrometastases.

Thus, as a further embodiment, the present invention provides the use ofa compound of formula (I) or subformulae thereof, e.g., compounds ofFormula II or III, in therapy. In a further embodiment, the therapy isselected from a disease which is ameliorated by inhibition of VEGFreceptor activity. In another embodiment, the disease is selected fromthe afore-mentioned list, suitably ocular diseases, more suitably wetand dry age-related macular degeneration, geographic atrophy, centralserous retinopathy, cystoid macular edema, diabetic retinopathy,proliferative diabetic retinopathy, diabetic macular edema, rubeosisiridis, Retinopathy of prematurity, Central and branch retinal veinocclusions, Inflammatory/infectious retinal neovascularization/edema(e.g. posterior uveitis, sarcoid, toxoplasmosis, histoplasmosis,Vogt-Koyanagi-Harada Disease, chronic uveitis, tuberculsosis, syphyllis,punctate and multifocal inner choroidopathy), retinoblastoma, melanoma,ocular tumors, retinal detachment, myopic neovascularization, angiodstreaks, Eales disease, ischemic retinopathy (Retinal artery occlusion,Takayasu's, carotid artery occlusion), choroidal rupture, contact lenswear, dry eye, blepharitis, corneal dystrophies, Trauma and previoussurgery to the cornea (corneal grafts, LASIK, LASEK), corneal infections(bacterial, viral, parasitic, herpetic), corneal burns (chemical,alkali, acid), corneal graft rejection, Immunological corneal disease(pemhigoid, stevens-Johnsons syndrome), and degenerative cornealdiseases.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10⁻³ molarand 10⁻⁹ molar concentrations. A therapeutically effective amount invivo may range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

In other embodiments, a pharmaceutical composition is provided whichcomprises at least one compound according to any one of Formulae I, II,III, IV, V, or VI, or a subformulae thereof and at least one carrier.

In other embodiments, a combination, in particular a pharmaceuticalcombination, is provided which comprising a therapeutically effectiveamount of the compound according to any one of claims 1 to 16 and one ormore therapeutically active agents selected from

A compound of the formula I may also be used to advantage in combinationwith other antiproliferative agents. Such antiproliferative agentsinclude, but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive agents; alkylating agents; historic deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; agents used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors; temozolomide (ILMODAL®); and leucovorin.

A compound of the formula I may also be used to advantage in combinationwith other ophthalmic therapeutics including but not limited to Macugen,VEGF trap, photodynamic therapy, anecortave Acetate, Steroids,non-steroidal anti-inflammatory (e.g. Naproxen, ibuprofen, diclofenac)Cox-1 and Cox-2 inhibitors, cyclosporine, dexamethasone, mtor (mammaliantarget of rapamycin) inhibitors such as rapamycin, everolimus, and thelike, PKC (protein kinase C) beta inhibitors, Tumor necrosis alphainhibitors, interleukin one beta inhibitors, platelet derived growthfactor beta and alpha and receptors inhibitors, Lucentis, Avastin, VEGFantibodies, PLGF antibodies, siRNA against VEGF family (A-E, PLGF,neuropilin)/VEGF receptors, complement inhibitors targeting classical,alternative and lectin pathways, IL-10 inhibitors, C5aR inhibitors, C3aRinhibitors, and inhibitors of sphingosine phosphate and receptors.

The compound of the present invention may be administered eithersimultaneously with, or before or after, at least one other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition.

In one embodiment, the other therapeutic agent is selected from:

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX. Abarelixcan be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing agents and microtublin polymerizationinhibitors including, but not limited to taxanes, e.g. paclitaxel anddocetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastinesulfate, vincristine especially vincristine sulfate, and vinorelbine,discodermolides, cochicine and epothilones and derivatives thereof, e.g.epothilone B or D or derivatives thereof. Paclitaxel may be administerede.g. in the form as it is marketed, e.g. TAXOL. Docetaxel can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark TAXOTERE. Vinblastine sulfate can be administered, e.g., inthe form as it is marketed, e.g. under the trademark VINBLASTIN R.P.Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide can be administered, e.g., in the form as itis marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds disclosed in WO02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes Suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil (5-FU); capecitabine; gemcitabine; DNA de-methylatingagents, such as 5-azacytidine and decitabine; methotrexate; edatrexate;and folic acid antagonists such as pemetrexed. Capecitabine can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR. Also included is themonoclonal antibody trastuzumab which can be administered, e.g., in theform as it is marketed, e.g. under the trademark HERCEPTIN.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity and further anti-angiogenic compounds” as used herein includes,but is not limited to: protein tyrosine kinase and/or serine and/orthreonine kinase inhibitors or lipid kinase inhibitors, e.g.:

a) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factor-receptors (FGF-Rs);b) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor I receptor (IGF-IR), especially compoundswhich inhibit the IGF-IR, such as those compounds disclosed in WO02/092599;c) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family;d) compounds targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family;e) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor;f) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK and Ras/MAPK familymembers, or PI(3) kinase family, or of the PI(3)-kinase-related kinasefamily, and/or members of the cyclin-dependent kinase family (CDK) andare especially those staurosporine derivatives disclosed in U.S. Pat.No. 5,093,330, e.g. midostaurin; examples of further compounds includee.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed in WO00/09495; FTIs; PD184352 or QAN697 (a PI3K inhibitor);g) compounds targeting, decreasing or inhibiting the activity of aprotein-tyrosine kinase, such as imatinib mesylate (GLIVEC/GLEEVEC) ortyrphostin. A tyrphostin is preferably a low molecular weight (Mr<1500)compound, or a pharmaceutically acceptable salt thereof, especially acompound selected from the benzylidenemalonitrile class or theS-arylbenzenemalonirile or bisubstrate quinoline class of compounds,more especially any compound selected from the group consisting ofTyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748;Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); andh) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGF-R,ErbB2, ErbB3, ErbB4 as homo- or heterodimers), such as compounds whichtarget, decrease or inhibit the activity of the epidermal growth factorreceptor family are especially compounds, proteins or antibodies whichinhibit members of the EGF receptor tyrosine kinase family, e.g. EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,and are in particular those compounds, proteins or monoclonal antibodiesgenerically and specifically disclosed in WO 97/02266, e.g. the compoundof ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP0 787 722, EP 0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g.compound known as CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO95/03283 (e.g. compound ZM105180); e.g. trastuzumab (HERCEPTIN),cetuximab, Iressa, erlotinib (Tarceva™), CI-1033, EKB-569, GW-2016,E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO03/013541.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (THALOMID) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,PTEN or CDC25, e.g. okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes are e.g. retinoicacid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol.

The term “cyclooxygenase inhibitor” as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA™.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulphate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor”, e.g. L-744832, DK8G557 or R115777 (Zamestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. PS-341 and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP inhibitor”) asused herein includes, but is not limited to collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “agents used in the treatment of hematologic malignancies” asused herein includes, but is not limited to FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of Flt-3; interferon, 1-b-D-arabinofuransylcytosine (ara-c) andbisulfan; and ALK inhibitors e.g. compounds which target, decrease orinhibit anaplastic lymphoma kinase.

The term “compounds which target, decrease or inhibit the activity ofFlt-3” are especially compounds, proteins or antibodies which inhibitFlt-3, e.g. PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteasome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to trastuzumab (Herceptin™), Trastuzumab-DM1, ranibizumab(Lucentis®) bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553(anti-CD40) and 2C4 Antibody. By antibodies is meant e.g. intactmonoclonal antibodies, polyclonal antibodies, multispecific antibodiesformed from at least 2 intact antibodies, and antibodies fragments solong as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of formulaI can be used in combination with standard leukemia therapies,especially in combination with therapies used for the treatment of AML.In particular, compounds of formula I can be administered in combinationwith e.g. farnesyl transferase inhibitors and/or other drugs useful forthe treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

The above-mentioned compounds, which can be used in combination with acompound of the formula I, can be prepared and administered as describedin the art such as in the documents cited above.

A compound of the formula I may also be used to advantage in combinationwith known therapeutic processes, e.g., the administration of hormonesor especially radiation.

A compound of formula I may in particular be used as a radiosensitizer,especially for the treatment of tumors which exhibit poor sensitivity toradiotherapy.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition mediated by VEGF or a VEGF receptor activity. Productsprovided as a combined preparation include a composition comprising thecompound of formula (I) and the other therapeutic agent(s) together inthe same pharmaceutical composition, or the compound of formula (I) andthe other therapeutic agent(s) in separate form, e.g. in the form of akit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I)in the manufacture of a medicament for treating a disease or conditionmediated by VEGF or a VEGF receptor activity, wherein the medicament isprepared for administration with another therapeutic agent. Theinvention also provides the use of a another therapeutic agent in themanufacture of medicament for treating a disease or condition mediatedby VEGF or a VEGF receptor activity], wherein the medicament is preparedfor administration with a compound of formula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a disease or condition mediated by VEGF or a VEGFreceptor activity, wherein the compound of formula (I) is prepared foradministration with another therapeutic agent. The invention alsoprovides another therapeutic agent for use in a method of treating adisease or condition mediated by VEGF or a VEGF receptor activity,wherein the other therapeutic agent is prepared for administration witha compound of formula (I). The invention also provides a compound offormula (I) for use in a method of treating a disease or conditionmediated by VEGF or a VEGF receptor activity, wherein the compound offormula (I) is administered with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition mediated by VEGF or a VEGF receptoractivity, wherein the other therapeutic agent is administered with acompound of formula (I).

The invention also provides the use of a compound of formula (I) in themanufacture of a medicament for treating a disease or condition mediatedby VEGF or a A a VEGF receptor, wherein the patient has previously (e.g.within 24 hours) been treated with another therapeutic agent. Theinvention also provides the use of another therapeutic agent in themanufacture of a medicament for treating a disease or condition mediatedby VEGF or the receptor thereof, wherein the patient has previously(e.g. within 24 hours) been treated with a compound of formula (I).

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

Based on the property of the compounds of formula I as potent VEGFreceptor inhibitors, the compounds of formula I are especially suitablefor the treatment of diseases associated with deregulated angiogenesis,especially diseases caused by ocular neovascularisation, especiallyretinopathies such as diabetic retinopathy or age-related maculadegeneration, psoriasis, Von Hippel Lindau disease, hemangioblastoma,angioma, mesangial cell proliferative disorders such as chronic or acuterenal diseases, e.g. diabetic nephropathy, malignant nephrosclerosis,thrombotic microangiopathy syndromes or transplant rejection, orespecially inflammatory renal disease, such as glomerulonephritis,especially mesangioproliferative glomerulonephritis, haemolytic-uraemicsyndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma,arterial restenosis, autoimmune diseases, acute inflammation, includingrheumatoid arthritis, fibrotic disorders (e.g. hepatic cirrhosis),diabetes, endometriosis, chronic asthma, arterial orpost-transplantational atherosclerosis, neurodegenerative disorders,e.g. multiple sclerosis, and especially neoplastic diseases such ascancer (especially solid tumours but also leukemias), such as especiallybreast cancer, adenocarcinoma, colorectal cancer, lung cancer(especially non-small-cell lung cancer), renal cancer, liver cancer,pancreatic cancer, ovarian cancer or cancer of the prostate as well asmyeloma, especially multiple myeloma, myelodysplastic syndrome, AIVIL(acute myeloid leukemia), AMM (agnogenic myeloid metaplasia),mesothelioma, glioma and glioblastoma. A compound of formula I isespecially suited also to preventing the metastatic spread of tumoursand the growth of micrometastases. The compounds of the formula I, dueto their activity as kinases, are also useful as in treatment inconnection with transplantation.

The following Examples serve to illustrate the invention withoutlimiting the scope thereof.

General Synthetic Aspects

Typically, the compounds of formula (I) can be prepared according to theSchemes provided infra.

Compounds such as 7 (wherein R₁ is H or alkyl, R₈ and R₉ are substitutedalkyl, H or taken together to be heterocyclic, Ar₂ is substitutedphenyl, heteroaryl, or heterocyclyl, R₅ and R₆ are H or halo, Z₂ is N orCH) can be prepared by the general method outlined in scheme 1. Couplingof hydroxyl indole 1 to the functionalized pyrimidine or pyridine 2(wherein LG is halo or the like or an activated alcohol) is accomplishedby treatment of with a suitable base (such as DBU) in a solvent (such asacetonitrile) either at rt or with heating preferably at a temperaturebetween rt and reflux to provide 3. Formation of urea 7 can be achievedby several methods such as, treatment of 3 with a suitable base (such asNaH or LiTMP) in a solvent (such as DMF or THF) preferably at 0° C. upto rt followed by the addition of an isocyanate 4 or an activatedcarbamate 5 (wherein Ar₂ is phenyl or substituted phenyl).Alternatively, 7 can be prepared by pre activation of either 3 or 6 witha coupling reagent (CR) such as CDI or the like followed by coupling tothe other component facilitated by a suitable base (such as Et₃N, NaH).

Compounds such as 10 (wherein R₁, Ar₂, and R₅ and R₆ are as describedabove, R₁₁ and R₁₂ are H or alkyl, and R₁₃ and R₁₄ are H, alkyl,substituted alkyl, aryl, heteroaryl, heterocyclyl or taken together tobe heterocyclyl or hetereoaryl and M is N or —S(O₂)—) are prepared bythe general method depicted in Scheme 2. Compound 8 is formed bydeprotection of 7a upon treatment with an acid (TFA, MsOH or the like)followed by conversion of the resulting alcohol to a suitable LG(mesylate, halo or the like). Carbonyl 8a can be prepared by oxidation(with DMP or the like) of the previous alcohol to give the aldehyde(R₂═H) or a sequence of oxidation to the aldehyde followed by theaddition of an alkyl organometallic reagent (such as an alkyl grignard)followed by a second oxidation to provide the correspondingketo-compound 8a (R₂=alkyl). Treatment of nucleophile 9 with a suitablebase (Et₃N, NaH or the like) and 8 between 0° C. and reflux in asuitable solvent provides 10. Alternatively, 10 can be prepared byreaction with 9 under reductive amination conditions (Na(AcO)₃BH or thelike) with carbonyl 8a.

Compounds such as 12 (wherein R₁, Ar₂, and R₅ and R₆ are as describedabove, R₁₉ and R₂₁ are H, or alkyl, R₂₀ is alkyl, acyl, or sulfonyl andp is 0 or 1) are prepared by the general method depicted in Scheme 3.Compound II is formed by deprotection of 7b (wherein R₃ is a suitablenitrogen protecting group such as tert-butyl carbamate) upon treatmentwith an acid (TFA or the like). The free amine in 11 is then alkylated,acylated or sulfonlyated to give compound 12.

Compounds of type 15 (wherein R₁, Ar₂, and R₅ and R₆ are defined asdescribed above and R₁₀ is alkyl, substituted alky, carboxylic amide,ester or acid) are generally prepared as described in Scheme 4. Couplingof hydroxyl indole 1 to the functionalized pyrimidine or pyridine 13(wherein LG is halo, the like or an activated alcohol and Y is halo,alkyl or carboxyl) is accomplished by treatment of with a suitable base(such as DBU, NaH, NaOH or the like) in a suitable solvent either at rtor with heating preferably at a temperature between it and refluxfollowed by subsequent urea formation, generally as described in Scheme1, to give 14. Further modification of Y (such as reduction, amidation,hydrolysis, and organometallic coupling) in compound 14 providescompounds of type 15.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

With the groups of preferred compounds of formula I mentionedhereinafter, definitions of substituents from the general definitionsmentioned hereinbefore may reasonably be used, for example, to replaceone or more up to all more general definitions with more specificdefinitions or especially with definitions characterized as beingpreferred.

Compounds of formula I are prepared analogously to methods that, forother compounds, are in principle known in the art, but are novel whenapplied in the manufacture of the compounds of the present invention,and are especially prepared according to the methods describedhereinbelow under ‘Examples’ or by analogous methods.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999. Corresponding protecting groups can be introduced, used andremoved at appropriate stages at any stage in the manufacture of acompound of the formula I.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

Abbreviations

-   ACN acetonitrile-   app apparent-   aq aqueous-   atm atmosphere-   ATP adenosine 5′-triphosphate-   BOC tertiary butyl carboxy-   BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexafluorophosphate-   br broad-   BSA bovine serum albumin-   d doublet-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2-dichloroethane-   dd doublet of doublets-   DCM dichloromethane-   DIEA diisopropylethylamine-   DMAP 4,4-dimethylaminopyridine-   DME 1,4-dimethoxyethane-   DMF N,N-dimethylformamide-   DMP Dess-Martin reagent;    1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one-   DMSO dimethylsulfoxide-   DTT dithiothreitol-   EDTA ethylenediamine tetraacetic acid-   ESI electrospray ionization-   EtOAc ethyl acetate-   FCC flash column chromatography-   g grams-   h hour(s)-   HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate methanaminium-   HBTU    1-[bis(dimethylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide-   HOBt 1-hydroxy-7-azabenzotriazole-   HPLC high pressure liquid chromatography-   IR infrared spectroscopy-   LCMS liquid chromatography and mass spectrometry-   LTMP lithium 2,2′,6,6′-tetramethylpiperidine-   M molar-   m multiplet-   MeOH methanol-   min minutes-   mL milliliter(s)-   mmol millimoles-   MS mass spectrometry-   MsOH methanesulfonic acid-   MW microwave-   m/z mass to charge ratio-   N normal-   NMR nuclear magnetic resonance-   Pd/C palladium on carbon-   ppm parts per million-   PyBOP benzotriazol-1-yloxytripyrrolidinophosphonium    hexafluorophosphate-   rac racemic-   rt room temperature-   R_(t) retention time-   s singlet-   sat saturated-   SFC Supercritical Fluid Chromatography-   t triplet-   TBSCl tert-butyldimethylsilyl chloride-   TFA trifluoroacetic acid-   THF tetrahydrofuran

EXAMPLE 1 2-Methyl-1H-indol-5-ol

To a precooled (0° C.) solution of 5-methoxy-2-methyl-1H-indole (5.0 g,31.0 mmol) in 100 mL DCM is added BBr₃ (1 M solution, 46.5 mL) under adry nitrogen atmosphere. The solution is then allowed to slowly warm toroom temperature over a 2 h period. The solution is then poured intowater, neutralized to pH 7 with sat aq sodium bicarbonate solution andextracted with EtOAc. The extract is washed by brine, dried over sodiumsulfate, and concentrated to give 2-methyl-1H-indol-5-ol. MS (ESI) m/z148.2 (M+1).

EXAMPLE 2 6-Fluoro-1H-indol-5-ol 2-A.1-Benzyloxy-2-fluoro-3-methyl-4-nitro-benzene

To a suspension of potassium carbonate (19.2 g, 138 mmol) and benzylalcohol (22 mL) is added 1,2-difluoro-3-methyl-4-nitrobenzene (12 g, 69mmol, ref. WO2007121416) and the mixture is heated to 180° C. for 2 h.The reaction mixture is then diluted with EtOAc and washed with water.The organic layer is concentrated and the residue is separated with FCC(EtOAc/heptane from 0 to 20%) to give1-benzyloxy-2-fluoro-3-methyl-4-nitrobenzene. ¹H NMR (400 MHz, MeOD) δppm 7.87 (dd, J=9.35, 2.02 Hz, 1H), 7.44-7.47 (m, 2H), 7.32-7.41 (m,3H), 7.17 (t, J=8.72 Hz, 1H), 5.26 (s, 2H), 2.49 (d, J=2.78 Hz, 3H).

2-B. 4-Fluoro-1H-indol-5-ol

1-Benzyloxy-2-fluoro-3-methyl-4-nitrobenzene (5 g, 19 mmol) is dissolvedN,N-dimethylformamide dimethyl acetal (15 mL) and heated in a microwavereactor at 180° C. in a sealed vial for 1 hour. The solution is thenconcentrated under reduced pressure. The resulting residue is dissolvedin THF and Pd/C (1.0 g, 10%, 0.95 mmol) is added. The mixture is stirredunder a hydrogen atmosphere at room temperature for 16 h before beingfiltered through a pad of Celite® and concentrated. The residue isseparated by FCC (EtOAc/heptane from 0 to 40%) to give4-fluoro-1H-indol-5-ol (1.5 g, 52% yield). MS (ESI) m/z 152.1 (M+1); ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.02 (br. s., 1H), 8.79 (s, 1H), 7.26 (t,J=2.78 Hz, 1H), 7.00 (d, J=8.59 Hz, 1H), 6.75 (t, J=8.46 Hz, 1H), 6.34(m, 1H).

2-C. 6-Fluoro-1H-indol-5-ol

6-Fluoro-1H-indol-5-ol is synthesized according to ref WO2003064413. MS(ESI) m/z 152.1 (M+1).

EXAMPLE 35-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-2H-pyrazol-3-ylamine3-A. 3-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionic acidmethyl ester

3-Hydroxy-2,2-dimethyl-propionic acid methyl ester (5 g, 37.8 mmol),imidazole (3.86 g, 56.8 mmol), and 4-pyrrolidinopyridine (193 mg, 1.32mmol) are combined in DCM (400 mL) before tert-butyldimethylsilylchloride (6.84 g, 45.4 mmol) is added. The mixture is then stirred at rtfor 4 h. The mixture is then partitioned between DCM and saturatedaqueous NaHCO₃. The organic layer separated, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The residue is then separated via FCC(heptanes to EtOAc/heptanes 5:95) to give the product as an oil (6.4 g,69%). ¹H NMR (400 MHz, CDCl₃) δ ppm 3.63 (s, 3H) 3.54 (s, 2H) 1.13 (s,6H) 0.85 (s, 9H), 0.00 (s, 6H).

3-B.5-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-3-oxo-pentanenitrile

A solution of n-butyllithium (17.9 mL, 28.6 mmol, 1.6 M in heptane) isadded to a precooled (−78° C.) solution of diisopropylamine (4.26 mL,29.9 mmol) and THF (45 mL). After 30 min a combination of3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionic acid methylester (3.2 g, 12.9 mmol) and acetonitrile (1.35 mL, 26 mmol) is added.The content of the flask are allowed to warm to rt and the pH is thenadjusted to 8 by the addition of 4 N HCl. The mixture is thenpartitioned between DCM and saturated aqueous NaHCO₃. The organic layeris separated and dried over anhydrous Na₂SO₄, filtered, and concentratedto provide the title compound. MS (ESI) m/z 256.1 (M+1).

3-C.5-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-2H-pyrazol-3-ylamine

A solution of5-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-3-oxo-pentanenitrile(3.32 g, 12.9 mmol), hydrazine (0.62 g, 19.5 mmol), and MeOH (50 mL) isheated at 70° C. for 6 h. The solution is then concentrated in vacuo andthe residue is separated via FCC (50-100% EtOAc/heptanes) to obtain thetitle compound. MS (ESI) m/z 270.3 (M+1).

EXAMPLE 4 4-Methyl-tetrahydro-pyran-4-carboxylic acid methyl ester

To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml)at −78° C., n-BuLi (25.2 ml, 1.6 M in heptane) is added. The reaction isremoved from the bath and stirred for 10 min. It is then cooled to −78°C. again and methyl tetrahydro-2H-pyran-4-carboxylate (6.48 ml, 48.6mmol) is added. After 30 min, iodomethane (6.07 ml, 97 mmol) is addedand the reaction allowed to reach rt. The reaction is then quenched with1 N HCl (200 mL) and extracted with EtOAc. The organic layer is driedand evaporated to give 4-methyl-tetrahydro-pyran-4-carboxylic acidmethyl ester. MS (ESI) m/z 159.3 (M+1).

EXAMPLE 53-(1-Methyl-cyclopropyl)-5-phenoxycarbonylamino-pyrazole-1-carboxylicacid tert-butyl ester 5-A. 3-(1-Methyl-cyclopropyl)-3-oxo-propionitrile

A solution of n-butyllithium (18.1 mL, 28.9 mmol, 1.6 M in heptane) isadded to a precooled (−78° C.) solution of diisopropylamine (4.31 mL,30.2 mmol) and THF (60 mL). After 30 min a combination of1-methyl-cyclopropanecarboxylic acid methyl ester (1.5 g, 13.1 mmol) andacetonitrile (1.37 mL, 26.3 mmol) is added. The reaction is allowed towarm to room temperature and the pH is adjusted 8 by the addition ofAcOH. The mixture is then concentrated to provide the title compound. MS(ESI) m/z 173.9 (M+1).

5-B. 5-(1-Methyl-cyclopropyl)-2H-pyrazol-3-ylamine

A solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (1.0 g, 8.1mmol), hydrazine (0.52 g, 16.2 mmol) and MeOH (40 mL) is heated at 70°C. for 6 h. The solution is then concentrated in vacuo and purified viasemi-prep HPLC (X-Bridge C18; 10-100% ACN/H₂O with 0.1% NH₄OH) toprovide the title compound. Alternatively the crude residue can be usedin the next step as is without further purification. MS (ESI) m/z 137.9(M+1).

5-C. 5-Amino-3-(1-methyl-cyclopropyl)-pyrazole-1-carboxylic acidtert-butyl ester

BOC protection carried out as described in reference Tetrahedron Letters2003, 44, 4491.

MS (ESI) m/z 238.0 (M+1).

5-D.3-(1-Methyl-cyclopropyl)-5-phenoxycarbonylamino-pyrazole-1-carboxylicacid tert-butyl ester

To a solution of 5-amino-3-(1-methyl-cyclopropyl)-pyrazole-1-carboxylicacid tert-butyl ester (3.90 g, 16.4 mmol) and phenyl chloroformate (3.11mL, 24.6 mmol) in DCM (150 mL) is added 2,6-lutidine (5.74 mL, 49.3mmol). After 18 h the solution is diluted with DCM (100 mL) and washedwith 1 M HCl (250 mL). The organic layer is then dried (Na₂SO₄),filtered, and concentrated to provide the title compound. MS (ESI) m/z358.0 (M+1).

The following compounds are prepared with similar method.

MS (ESI) Structure/Chemical Name m/z (M − 1) 5-E

370.1 5-F

344.3 5-G

400.2 5-H

342.2 5-I

246.2 5-J

260.2 5-K

232.2 5-L

260.2 5-M

 260.19 5-N

258.2 5-O

286.2 5-P

300.1 5-Q

300.1 5-R

286.3 5-S

272.2

EXAMPLE 6 6-A. 3-Isopropyl-isoxazol-5-ylamine

A solution of hydroxylamine sulfate (1.72 g, 20.9 mmol) in water (4 mL)is added to a solution of 5-methyl-3-oxo-hexanenitrile (2.38 g, 19.0mmol) and sodium hydroxide (0.837 g, 20.9 mmol) in water (10 mL) at rt.After the mixture has been adjusted to pH 8.20 with 5% NaOH, it isheated to 100° C. for 1.5 h. At this point, concentrated hydrochloricacid (1.73 mL, 17.1 mmol) is added to the reaction mixture followed byheating at 100° C. for 15 min. After cooling, the pH is adjusted to 11with 30% NaOH and the mixture extracted with EtOAc (3×). The organicextracts are dried over Na₂SO₄ and concentrated to give5-isopropyl-isoxazol-3-ylamine. MS (ESI) m/z 127.2 (M+1).

The following compounds are prepared with similar method.

MS (ESI) Structure/Chemical Name m/z (M + 1) 6-B

179.3 6-C

161.2 6-D

139.2 6-E

167.5 6-F

141.5 (M − 1) 6-G

123.2 (M − 1) 6-H

139.2 6-I

155.5

EXAMPLE 7 7-A. 5-Isopropyl-isoxazol-3-ylamine

To a mixture of 4-methyl-3-oxopentanenitrile (11 g, 99 mmol) and water(200 mL) is added NaOH (4.95 g, 124 mmol). Once the NaOH pellets arecompletely dissolved, hydroxylamine sulfate (8.93 g, 109 mmol) is addedand after 5 min the pH is measured (pH 7-8). The reaction is warmed to40° C. and stirred for 72 h. At this point HCl (13.0 mL, 158 mmol, 37%)is added in one portion and the reaction warmed to 50° C. for 2.5 h. Thereaction is removed from the oil bath and allowed to cool to rt. At thispoint a solution of NaOH (30% in H₂O) is added to give a solution of pH11. EtOAc is then added and the layers separated. The water layer isextracted with EtOAc (3×) until no more product appears in the LCMS ofthe water layer. The combined organics are dried (Na₂SO₄) and evaporatedto give 5-isopropyl-isoxazol-3-ylamine. MS (ESI) m/z 127.2 (M+1).

The following compounds are prepared with similar method.

MS (ESI) Structure/Chemical Name m/z (M + 1) 7-B

151.2 (M − 1) 7-C

155.5 7-D

183.2 7-E

139.2 7-F

167.5 7-G

125.2 7-H

141.5 (M − 1) 7-I

169.3 7-J

209.1

EXAMPLE 8 8-A. 5-Phenyl-isoxazol-3-ylamine

Hydroxylamine sulfate (2.5 g, 30.3 mmol) is added to a stirred solutionof 3-oxo-3-phenylpropanenitrile (4 g, 27.6 mmol) and NaOH (1.27 g, 31.7mmol) in H₂O (25 mL)/EtOH (25 mL). The mixture is stirred at rt and thenheated to 80° C. for 22 h. At this point, conc. HCl (3.39 ml, 41.3 mmol)is added and the mixture heated at 80° C. for an additional 2 h. It isthen basified to pH 10 and extracted with EtOAc to give5-phenyl-isoxazol-3-ylamine. MS (ESI) m/z 161.2 (M+1).

The following compound are prepared with similar method.

8-B. 5-(4-Fluoro-phenyl)-isoxazol-3-ylamine

MS (ESI) m/z 179.3 (M+1).

EXAMPLE 93-(tert-Butyl-dimethyl-silanyloxymethyl)-5-trifluoromethyl-phenylamine

To a solution of 3-Amino-5-trifluoromethyl-benzoic acid (2.0 g, 9.76mmol) in THF (40 mL) at 0° C. is added LiAlH₄ in THF (1 M, 39 mL). Themixture is warmed to reflux and stirred for 62 h. The mixture is thencooled to 0° C. and NaF (2.2 g) is added followed by H₂O (3.8 mL). Theslurry is stirred for 10 minutes and then allowed to warm to rt and stiran additional 40 min. The mixture is filtered and the solid is rinsedwith EtOAc and MeOH. The filtrate is concentrated and the crude residueis mixed with imidazole (2.66 g, 39 mmol) and DCM (30 mL) at 0° C. TBSCl(3.5 g, 23.4 mmol) is added and the mixture is stirred at rt for 5 h.The reaction mixture is then diluted with EtOAc, washed with saturatedaqueous NaHCO₃, brine, and dried over Na₂SO₄. Concentration provides thetitle compound that is carried on to next step without furtherpurification. MS (ESI) m/z 306.1 (M+1).

EXAMPLE 10 5-Trifluoromethyl-pyridin-3-ylamine

A mixture of 2-chloro-5-nitro-3-trifluoromethyl-pyridine (30 mg, 0.13mmol), 10% Pd/C (3 mg, 10% w/w), and MeOH (5 mL) is stirred under 1 atmof hydrogen for 3 h. The mixture is then filtered over Celite® andconcentrated in vacuo to give the title compound as an oil. MS (ESI) m/z162.9 (M+1).

EXAMPLE 11 3-Amino-N-isopropyl-5-(trifluoromethyl)benzamide

To a solution of 3-amino-5-(trifluoromethyl)benzoic acid (0.25 g, 1.22mmol) in DMF (3 mL) is added HOBt (0.494 g, 3.66 mmol) followed by HATU(0.695 g, 1.83 mmol), propan-2-amine (0.311 mL, 3.66 mmol) and DIEA(0.96 mL, 5.48 mmol). After stirring at it overnight the solution isconcentrated and the residue is dissolved in EtOAc, washed with sat aqNaHCO₃, brine, and dried over Na₂SO₄. Following concentration theresidue is carried on to next step without further purification. MS(ESI) m/z 247.1 (M+1).

EXAMPLE 12 3-Amino-5-trifluoromethyl-benzonitrile

To a solution of 3-nitro-5-(trifluoromethyl)benzonitrile (500 mg, 2.31mmol) and acetic acid (6.62 mL, 116 mmol) in EtOH (10 mL) and water (10mL) is added tin (II) chloride (2.61 g, 11.6 mmol) and the reactionmixture is heated at 80° C. for 6 h. The solvent is removed in vacuo andthen the residue is portioned between DCM and 4 N HCl solution. Theorganic layer separated and then dried over anhydrous Na₂SO₄, filteredand concentrated. The residue is then separated via FCC (10-100%EtOAc/heptane) to give the compound as a yellow oil (213 mg, 49%). MS(ESI) m/z 185.3 (M+1).

EXAMPLE 13 13-A. (5-Trifluoromethyl-pyridin-3-yl)-carbamic acid phenylester

Example 7-A, 5-trifluoromethyl-pyridin-3-ylamine, (385 mg, 2.37 mmol) istaken up in THF (25 mL) and pyridine (0.38 mL, 4.75 mmol) at 0° C.before phenyl chloroformate (558 mg, 3.56 mmol) is added. After 2 h, thereaction is diluted with DCM (50 mL) and washed with water (50 mL). Theorganic layer is separated, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue is then separated via FCC (EtOAc/heptanes 1:9to EtOAc/heptanes 1:1) to give the title compound. MS (ESI) m/z 283.0(M+1).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name (M + 1) 13-B

367.1 13-C

426.1 13-D

247.3 13-E

261.2 13-F

305.0 13-G

261.2 13-H

281.2 13-I

299.1 13-J

259.2 13-K

275.2 13-L

261.3 13-M

259.2 13-N

245.2 13-O

339.1 13-P

259.2 13-Q

261.2 13-R

281.2 13-S

299.1 13-T

259.2 13-U

275.2 13-V

261.3 13-W

247.3 13-X

245.2 13-Y

303.2 13-Z

287.2 13-AA

289.2 13-AB

287.2 13-AC

219.2 13-AD

329.0

EXAMPLE 14 14-A. 5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole

To a solution of 5-hydroxy indole (1.33 g, 10 mmol) and4-benzyloxymethyl-6-chloro-pyrimidine (2.35 g, 10 mmol) in acetonitrile(20 mL) is added DBU. After 16 h at rt the solution is concentratedunder reduced pressure. The residue is purified by FCC (EtOAc/Heptanefrom 0% to 40%) to give546-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole. MS (ESI) m/z 447.0(M+1).

The following compounds are prepared with similar method.

14-B.5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole

MS (ESI) m/z 364.0 (M+1)

14-C. 5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-4-fluoro-1H-indole

MS (ESI) m/z 350.2 (M+1)

EXAMPLE 15 15-A.5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide

To a solution of 2,2,6,6-tetramethyl-piperidine (1.07 g, 7.6 mmol) inTHF (40 mL) at −78° C. is added n-butyllithium (2.5 M in hexane, 2.9 mL)followed by 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole (2.4 g,7.3 mmol) while keeping the temperature below −70° C. The reaction isstirred for 10 min before1-fluoro-4-isocyanato-2-trifluoromethyl-benzene (1.56 g, 7.6 mmol) isadded and then the solution is allowed to slowly warm to rt and stir foran additional 16 h. The solvent is then removed under reduced pressureand the residue partitioned between EtOAc and water. The organic layeris separated, dried and concentrated. The residue is then separated viaFCC (EtOAc/heptane from 0% to 100%) to give the title compound. MS (ESI)m/z 537.0 (M+1).

The following compounds are prepared with similar method.

MS (ESI) Structure/Chemical Name m/z (M + 1) 15-B

519.2 15-C

537.0 15-D

537.0 15-E

551.0 15-F

537.0

EXAMPLE 16 16-A.5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide

A solution of5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide (2.0 g, 3.7 mmol) in TFA (20mL) is heated at 60° C. for 24 h before being allowed to cool to rt. Thesolution is then poured onto 100 g crushed ice. The oily product isremoved and then separated by FCC (EtOAc/Heptane from 0% to 100%) toprovide the title compound. MS (ESI) m/z 447.0 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.40 (s, 1H), 8.65 (d, J=1.01 Hz, 1H), 8.29 (d, J=9.09Hz, 1H), 8.09-8.12 (m, 2H), 8.99-8.04 (m, 1H), 7.58 (t, J=9.60 Hz, 1H),7.51 (d, J=2.53 Hz, 1H), 7.16 (dd, J=8.84, 2.53 Hz, 1H), 6.99 (d, J=1.01Hz, 1H), 6.82 (d, J=3.79 Hz, 1H), 5.61 (t, J=5.05 Hz, 1H), 4.52 (d,J=5.05 Hz, 2H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 16-B

(MeOD) δ ppm 8.61 (d, J = 1.01 Hz, 1H), 8.37 (d, J = 8.84 Hz, 1H), 8.07(s, 1H), 7.96 (d, J = 3.79 Hz, 1H), 7.90 (dd, J = 7.96, 1.39 Hz, 1H),7.58 (t, J = 7.96 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 2.27 Hz, 1H), 7.13(dd, J = 8.97, 2.40 Hz, 1H), 7.08 (d, J = 1.01 Hz, 1H), 6.76 (d, J =3.79 Hz, 1H), 4.63 (s, 2H). 429.1 16-C

(DMSO-d₆) δ ppm 10.28 (s, 1H), 8.65 (d, J = 1.01 Hz, 1H), 8.27 (d, J =8.84 Hz, 1H), 8.11 (d, J = 3.79 Hz, 1H), 7.92-7.96 (m, 1H), 7.68-7.73(m, 1H), 7.47-7.52 (m, 2H), 7.16 (dd, J = 8.97, 2.40 Hz, 1H), 6.98 (d, J= 1.01 Hz, 1H), 6.83 (d, J = 3.79 Hz, 1H), 5.60-5.62 (m, 1H), 4.52 (d, J= 5.81 Hz, 2H). 466.9 16-D

(DMSO-d₆) δ ppm 10.27 (s, 1H), 8.65 (d, J = 1.01 Hz, 1H), 8.27 (d, J =8.84 Hz, 1H), 8.10 (d, J = 3.79 Hz, 1H), 8.05 (dd, J = 6.95, 2.15 Hz,1H), 7.72 (d, J = 4.04 Hz, 1H), 7.62 (t, J = 9.35 Hz, 1H), 7.51 (d, J =2.27 Hz, 1H), 7.16 (dd, J = 8.97, 2.40 Hz, 1H), 6.98 (d, J = 1.01 Hz,1H), 6.82 (d, J = 3.79 Hz, 1H), 5.61 (t, J = 5.68 Hz, 1H), 4.52 (d, J =5.31 Hz, 2H). 446.9 16-E

(DMSO-d₆) δ ppm 10.49 (s, 1H) 8.65 (s, 1H), 8.08-8.19 (m, 3H), 7.97 (d,J = 8.59 Hz, 1H) 7.66 (t, J = 8.08 Hz, 1H) 7.52 (d, J = 7.83 Hz, 1H),7.27-7.34 (m, 1H) 7.17 (s, 1H) 6.94 (d, J = 3.54 Hz, 1H), 5.68 (br. S,1H) 4.57 (s, 2H). 447.0

EXAMPLE 17 17-A.4-Fluoro-5-(6-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

A solution of5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-4-fluoro-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (2.0 g, 3.6 mmol) and MsOH (15 mL)is heated at 100° C. for 8 min before being poured into saturatedaqueous NaHCO₃. The aqueous phase is extracted with EtOAc. The organicphase is washed with brine, dried over anhydrous Na₂SO₄, and purifiedvia FCC (EtOAc/heptanes 2:8 to EtOAc) to give the title compound. MS(ESI) m/z 461.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.00 (s, 1H)8.61-8.65 (m, 1H) 8.12 (s, 1H) 7.91 (s, 1H) 7.66 (t, J=7.71 Hz, 1H) 7.52(d, J=8.84 Hz, 1H) 7.12-7.22 (m, 2H) 6.84 (br. S., 1H) 6.63 (s, 1H) 5.66(t, J=5.94 Hz, 1H) 4.56 (d, J=5.56 Hz, 2H) 2.59 (s, 3H).

The following compound is prepared by a similar method.

17-B. [6-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-yl]-methanol

MS (ESI) m/z 274.2 (M+1).

EXAMPLE 18 18-A.5-(6-Methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide

To a solution of5-(6-hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide (260 mg, 0.6 mmol),methanesulfonic anhydride (240 mg, 1.4 mmol), and THF (15 mL) is addedpyridine (0.2 mL). The mixture is stirred at rt for 0.5 h before beingfiltered. The filtrate is used in the next step without purification. MS(ESI) m/z 525.0 (M+1).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name (M + 1) 18-B

507.0 18-C

524.8 18-D

524.8 18-E

538.8 18-F

352.0 18-G

525.0

EXAMPLE 19 19-A.5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide

To a solution of5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide, Example 18A, (180 mg, 0.35mmol) is added methyl amine (1 mL, 2.0 M in methanol). The mixture isstirred at room temperature for 16 h, then concentrated under reducedpressure. The residue is diluted with EtOAc and washed with water andbrine. The organic layer is removed, dried, and concentrated. Theresidue is then separated by FCC (MeOH with 1% NH₄OH/DCM from 0% to 10%)to give the title compound. MS (ESI) m/z 460.1 (M+1); ¹H NMR (400 MHz,MeOD) δ ppm 8.65 (d, J=1.01 Hz, 1H), 8.35 (d, J=8.84 Hz, 1H), 8.04 (dd,J=6.19, 2.65 Hz, 1H), 7.90-7.94 (m, 2H), 7.41 (d, J=2.27 Hz, 1H), 7.35(t, J=9.60 Hz, 1H), 7.11 (dd, J=8.97, 2.40 Hz, 1H), 7.00 (s, 1H), 6.74(d, J=3.79 Hz, 1H), 3.82 (s, 2H), 2.43 (s, 3H).

The following compounds are prepared with similar method starting fromcompounds of Example 18A-G.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 19-B

(MeOD) δ ppm 8.64 (s, 1H), 8.34 (d, J = 9.09 Hz, 1H), 8.05 (s, 1H), 7.93(d, J = 3.79 Hz, 1H), 7.89 (d, J = 8.08 Hz, 1H), 7.56 (t, J = 7.96 Hz,1H), 7.40-7.46 (m, 2H), 7.10 (dd, J = 8.97, 2.40 Hz, 1H), 6.99 (s, 1H),6.73 (d, J = 3.79 Hz, 1H), 3.77 (s, 2H), 2.40 (s, 3H). 442.1 19-C

(MeOD) δ ppm 8.65 (d, J = 1.01 Hz, 1H), 8.36 (d, J = 8.84 Hz, 1H), 8.05(dd, J = 6.19, 2.91 Hz, 1H), 7.91-7.95 (m, 2H), 7.42 (d, J = 2.27 Hz,1H), 7.36 (t, J = 9.60 Hz, 1H), 7.12 (d, J = 8.84, 2.53 Hz, 1H), 7.03(s, 1H), 6.75 (d, J = 3.79 Hz, 1H), 3.85 (s, 2H), 2.83 (m, 1H), 1.10 (d,J = 6.32 Hz, 6H). 488.0 19-D

(MeOD) δ ppm 8.64 (d, J = 1.01 Hz, 1H), 8.35 (d, J = 9.09 Hz, 1H), 8.04(dd, J = 6.32, 2.78 Hz, 1H), 7.92 (d, J = 3.79 Hz, 1H), 7.90-7.94 (m,1H), 7.41 (d, J = 2.27 Hz, 1H), 7.35 (t, J = 9.60 Hz, 1H), 7.11 (dd, J =8.97, 2.40 Hz, 1H), 7.02 (d, J = 1.01 Hz, 1H), 6.74 (d, J = 3.79 Hz,1H), 3.85 (s, 2H), 3.47-3.51 (m, 2H), 3.32 (s, 3H), 2.76-2.79 (m, 2H).504.0 19-E

(MeOD) δ ppm 8.62 (d, J = 1.01 Hz, 1H), 8.34 (d, J = 8.84 Hz, 1H), 8.05(s, 1H), 7.93 (d, J = 3.54 Hz, 1H), 7.89 (d, J = 8.08 Hz, 1H), 7.56 (t,J = 8.21 Hz, 1H), 7.40-7.45 (m, 2H), 7.09 (s, 1H), 7.02 (s, 1H), 6.73(d, J = 3.79 Hz, 1H), 3.65 (br. S., 1H), 3.67 (d, m, 4H), 3.58 (s, 2H),2.50 (d, m, 4H). 498.0 19-F

(MeOD) δ ppm 8.64 (s, 1H), 8.35 (d, J = 8.84 Hz, 1H), 8.06 (s, 1H), 7.94(d, J = 3.54 Hz, 1H), 7.90 (d, J = 8.08 Hz, 1H), 7.57 (t, J = 7.96 Hz,1H), 7.42 (d, J = 2.53 Hz, 2H), 7.11 (dd, J = 8.84, 2.27 Hz, 1H), 7.03(s, 1H), 6.74 (d, J = 3.54 Hz, 1H), 3.55 (s, 2H), 2.29 (s, 6H). 456.119-G

(MeOD) δ ppm 8.63 (d, J = 1.01 Hz, 1H), 8.36 (d, J = 8.84 Hz, 1H), 8.05(dd, J = 6.32, 2.78 Hz, 1H), 7.94 (d, J = 3.79 Hz, 1H), 7.91-7.95 (m,1H), 7.43 (d, J = 2.27 Hz, 1H), 7.36 (t, J = 9.47 Hz, 1H), 7.10-7.14 (m,2H), 6.75 (d, J = 3.79 Hz, 1H), 3.68 (m, 4H), 3.61 (s, 2H), 2.52 (m,4H). 516.0 19-H

(MeOD) δ ppm 8.64 (s, 1H), 8.35 (d, J = 9.09 Hz, 1H), 8.06 (s, 1H), 7.94(d, J = 3.54 Hz, 1H), 7.89 (d, J = 8.08 Hz, 1H), 7.56 (t, J = 8.08 Hz,1H), 7.40-7.46 (m, 2H), 7.10 (dd, J = 8.84, 2.27 Hz, 1H), 7.02 (s, 1H),6.74 (d, J = 3.79 Hz, 1H), 3.82 (s, 2H), 2.81 (quin, J = 6.25 Hz, 1H),1.09 (d, J = 6.32 Hz, 6H). 470.1 19-I

(MeOD) δ ppm 8.62 (d, J = 1.01 Hz, 1H), 8.34 (d, J = 8.84 Hz, 1H), 8.05(s, 1H), 7.93 (d, J = 3.54 Hz, 1H), 7.89 (d, J = 8.08 Hz, 1H), 7.56 (t,J = 8.21 Hz, 1H), 7.40-7.45 (m, 2H), 7.09 (s, 1H), 6.73 (d, J = 3.79 Hz,1H), 3.65 (br. S., 1H), 3.67 (d, m, 4H), 3.58 (s, 2H), 2.50 (d, m, 4H).498.0 19-J

(MeOD) δ ppm 8.63 (d, J = 1.01 Hz, 1H), 8.34 (d, J = 8.84 Hz, 1H), 8.05(s, 1H,) 7.93 (d, J = 3.79 Hz, 1H), 7.89 (d, J = 8.34 Hz, 1H), 7.56 (t,J = 8.08 Hz, 1H), 7.40-7.45 (m, 2H), 7.10 (dd, J = 8.97, 2.40 Hz, 1H),7.01 (s, 1H), 6.73 (d, J = 3.79 Hz, 1H), 3.84 (s, 2H), 3.47-3.50 (m,2H), 3.31 (s, 3H), 2.75-2.79 (m, 2H). 486.0 19-K

(MeOD) δ ppm 8.64 (d, J = 1.01 Hz, 1H), 8.36 (d, J = 8.84 Hz, 1H), 8.06(s, 1H), 7.95 (d, J = 3.79 Hz, 1H), 7.90 (d, J = 8.34 Hz, 1H), 7.57 (t,J = 7.96 Hz, 1H), 7.43 (d, J = 2.27 Hz, 2H), 7.12 (dd, J = 8.84, 2.27Hz, 1H), 7.05 (s, 1H), 6.75 (d, J = 3.79 Hz, 1H), 3.74 (s, 2H), 2.61 (m,4H), 1.81 (m, 4H). 482.0 19-L

(MeOD) δ ppm 8.64 (d, J = 1.01 Hz, 1H), 8.35 (d, J = 8.84 Hz, 1H), 8.06(s, 1H), 7.94 (d, J = 3.79 Hz, 1H), 7.89 (d, J = 8.08 Hz, 1H), 7.56 (t,J = 7.96 Hz, 1H), 7.40-7.45 (m, 2H), 7.10 (dd, J = 8.97, 2.40 Hz, 1H),7.03 (s, 1H), 6.74 (d, J = 3.79 Hz, 1H), 3.92 (ddd, J = 11.87, 4.04,2.02 Hz, 2H), 3.86 (s, 2H), 3.38 (td, J = 11.75, 2.02 Hz, 2H), 2.69 (tt,J = 10.74, 4.04 Hz, 1H), 1.83 (ddd, J = 12.63, 4.04, 2.02 Hz, 2H),1.35-1.45 (m, 2H). 512.0 19-M

(MeOD) δ ppm 8.64 (s, 1H), 8.35 (d, J = 8.84 Hz, 1H), 8.06 (s, 1H), 7.94(d, J = 3.54 Hz, 1H), 7.89 (d, J = 6.57 Hz, 1H), 7.57 (t, J = 8.21 Hz,1H), 7.41-7.46 (m, 2H), 7.11 (dd, J = 8.97, 2.40 Hz, 1H), 7.02 (s, 1H),6.74 (d, J = 3.79 Hz, 1H), 3.81 (s, 2H), 3.08 (quin, J = 6.88 Hz, 1H),1.81-1.91 (m, 2H), 1.65-1.76 (m, 2H), 1.50-1.60 (m, 2H), 1.32-1.44 (m,2H). 496.1 19-N

(MeOD) δ ppm 8.65 (d, J = 1.01 Hz, 1H), 8.37 (d, J = 8.84 Hz, 1H), 8.06(s, 1H), 7.95 (d, J = 3.79 Hz, 1H), 7.91 (d, J = 2.02 Hz, 1H), 7.58 (t,J = 7.96 Hz, 1H), 7.46 (s, 1H), 7.43 (d, J = 2.27 Hz, 1H), 7.12 (dd, J =8.97, 2.40 Hz, 1H), 7.02 (s, 1H), 6.75 (d, J = 3.79 Hz, 1H), 3.85 (s,2H), 2.73-2.77 (m, 2H), 2.61-2.65 (m, 2H), 2.54 (m, 4H), 1.79 (m, 4H).525.1 19-O

(MeOD) δ ppm 8.62 (d, J = 1.01 Hz, 1H), 8.36 (d, J = 9.09 Hz, 1H), 8.06(s, 1H), 7.95 (d, J = 3.79 Hz, 1H), 7.90 (d, J = 8.08 Hz, 1H), 7.56 (s,1H), 7.58 (t, J = 8.08 Hz, 1H), 7.41-7.46 (m, 2H), 7.11 (t, J = 1.39 Hz,1H), 7.11 (dd, J = 8.97, 2.40 Hz, 1H), 6.92-6.95 (m, 2H), 6.75 (d, J =3.79 Hz, 1H), 4.12 (t, J = 6.19 Hz, 2H), 3.82 (s, 2H), 2.97 (t, J = 6.19Hz, 2H). 522.0 19-P

(MeOD) δ ppm 8.64 (d, J = 1.01 Hz, 1H), 8.34 (d, J = 9.09 Hz, 1H), 8.05(s, 1H), 7.93 (d, J = 3.79 Hz, 1H), 7.89 (d, J = 8.08 Hz, 1H), 7.56 (t,J = 7.96 Hz, 1H), 7.39-7.45 (m, 2H), 7.09 (dd, J = 8.84, 2.27 Hz, 1H),7.00 (d, J = 1.01 Hz, 1H), 6.73 (d, J = 3.54 Hz, 1H), 3.87 (s, 2H),2.13-2.19 (m, 1H), 0.35-0.48 (m, 4H). 468.0 19-Q

(MeOD) δ ppm 8.67 (s, 1H), 8.37 (d, J = 8.84 Hz, 1H), 8.07 (s, 1H), 7.96(d, J = 3.79 Hz, 1H), 7.90 (d, J = 8.34 Hz, 1H), 7.58 (t, J = 8.08 Hz,1H), 7.43 (d, J = 2.53 Hz, 1H), 7.46 (s, 1H), 7.12 (dd, J = 8.97, 2.40Hz, 1H), 7.02 (s, 1H), 6.76 (d, J = 3.79 Hz, 1H), 3.95 (s, 2H), 3.53 (t,J = 6.32 Hz, 2H), 3.35 (t, J = 5.81 Hz, 2H), , 2.89 (t, J = 6.32 Hz,2H), 2.32 (t, J = 6.06 Hz, 2H), 1.74-1.82 (m, 4H). 553.1 19-R

(CD₂Cl₂) δ ppm 8.66 (s, 1H), 8.29 (d, J = 8.84 Hz, 1H), 7.96 (s, 1H),7.80 (s, 1H), 7.66 (d, J = 3.54 Hz, 1H), 7.60 (t, J = 7.96 Hz, 2H),7.49-7.52 (m, 1H), 7.45 (d, J = 2.02 Hz, 1H), 7.18 (dd, J = 8.84, 2.27Hz, 1H), 7.14 (br. S., 1H), 6.79 (d, J = 3.03 Hz, 1H), 3.71 (br. S.,2H), 3.60 (br. S., 2H), 2.74 (br. S., 2H), 1.91 (br. S., 2H), 1.15 (d, J= 6.32 Hz, 6H). 526.0 19-S

(DMSO-d₆) δ ppm 10.39 (br. S., 1H), 8.65 (d, J = 1.01 Hz, 1H), 8.29 (d,J = 8.84 Hz, 1H), 8.13 (d, J = 3.54 Hz, 1H), 8.10 (s, 1H), 7.98 (d, J =8.34 Hz, 1H), 7.65 (t, J = 8.08 Hz, 1H), 7.51 (s, 1H), 7.49 (d, J = 2.53Hz, 1H), 7.15 (dd, J = 8.97, 2.40 Hz, 1H), 7.10 (s, 1H), 6.81 (d, J =3.79 Hz, 1H), 4.50 (t, J = 5.31 Hz, 1H), 3.79 (s, 2H), 3.46 (q, J = 5.73Hz, 2H), 2.60 (t, J = 5.68 Hz, 2H). 472.0 19-T

(MeOD) δ ppm 8.65 (d, J = 1.01 Hz, 1H) 8.37 (s, 1H) 8.07 (s, 1H) 7.95(d, J = 3.79 Hz, 2H) 7.45 (d, J = 2.02 Hz, 1H) 7.38 (d, J =19.70 Hz, 1H)7.14 (dd, J = 9.09, 2.53 Hz, 1H) 7.12 (s, 1H) 6.78 (d, J = 3.79 Hz, 1H)4.37 (d, J = 7.83 Hz, 1H) 3.78 (d, J = 4.29 Hz, 2H) 3.50 (dt, J = 3.28,1.64 Hz, 1H) 3.15 (dt, J = 3.28, 1.64 Hz, 1H) 2.84 (d, J = 16.17 Hz, 2H)2.60 (s, 2H) 516.9 19-U

(CD₂Cl₂) δ ppm 8.70 (s, 1H), 8.29 (d, J = 8.84 Hz, 1H), 7.96 (s, 1H),7.80 (s, 1H), 7.66 (d, J = 3.79 Hz, 1H), 7.60 (s, 1H), 7.49-7.55 (m,2H), 7.45 (d, J = 2.53 Hz, 1H), 7.19 (dd, J = 9.09, 2.27 Hz, 1H), 6.99(s, 1H), 6.80 (d, J = 3.54 Hz, 1H), 4.00 (s, 2H), 3.27-3.34 (m, 2H).509.9 19-V

(MeOD) δ ppm 8.66 (s, 1H), 8.37 (d, J = 9.09 Hz, 1H) 8.06 (d, J = 6.06Hz, 1H) 7.95 (br. S., 2H) 7.44 (s, 1H) 7.37 (t, J = 9.47 Hz, 1H) 7.12(d, J = 1.77 Hz, 1H) 7.14 (s, 1H) 6.77 (br. S., 1H) 3.33 (m. S., 6H)3.24 (m, 4H) 563.1 19-W

(MeOD) δ ppm 8.65 (br. S., 1H) 8.38 (br. S., 1H) 8.07 (br. S., 1H) 7.95(br. S., 2H) 7.41 (s, 2H) 7.14 (br. S., 2H) 6.78 (s, 1H) 4.19 (d, J =16.0 Hz, 1H) 3.55 (d, J = 16.0 Hz, 1H) 3.54 (m, 3H), 3.04 (m, 1H) 2.76(m, 1H) 2.36 (m, 1H) 1.96 (m, 1H) 1.77 (m, 2H) 530.9 19-X

(MeOD) δ ppm 8.63 (s, 1H) 8.36 (d, J = 8.84 Hz, 1H) 8.05 (d, J = 6.32Hz, 1H) 7.93 (d, J = 3.79 Hz, 2H) 7.36 (t, J = 9.47 Hz, 1H) 7.43 (d, J =2.27 Hz, 1H) 7.12 (dd, J = 8.84, 2.27 Hz, 1H) 7.08 (s, 1H) 6.75 (d, J =3.54 Hz, 1H) 3.59 (m, 3H) 2.79 (m, 2H) 2.25 (m, 2H) 1.82 (m, 2H) 1.54(m, 2H) 530.9 19-Y

(MeOD) δ ppm 8.65 (d, J = 1.01 Hz, 1H), 8.35 (d, J = 9.09 Hz, 1H), 8.05(dd, J = 6.32, 2.78 Hz, 1H), 7.93 (d, J = 3.79 Hz, 1H), 7.91-7.95 (m,1H), 7.42 (d, J = 2.27 Hz, 1H), 7.36 (t, J = 9.73 Hz, 1H), 7.11 (dd, J =8.97, 2.40 Hz, 1H), 7.02 (s, 1H), 6.75 (d, J = 3.79 Hz, 1H), 3.88 (s,2H), 2.15-2.20 (m, 1H), 0.35-0.49 (m, 4H). 485.9 19-Z

(Aceton-d₆) δ ppm 9.60 (s, 1H), 8.63 (s, 1H), 8.40 (d, J = 9.09 Hz, 1H),8.18 (dd, J = 6.32, 2.78 Hz, 1H), 8.05 (d, J = 3.79 Hz, 1H), 8.04-8.11(m, 1H), 7.45-7.51 (m, 2H), 7.18 (dd, = 8.97, 2.40 Hz, 1H), 7.12 (s,1H), 6.79 (d, J = 3.54 Hz, 1H), 4.00-4.03 (m, 2H), 3.36-3.45 (m, 2H).527.9 19-AA

(MeOD) δ ppm 8.62 (s, 1H) 8.33 (d, J = 9.09 Hz, 1H) 8.03 (dd, J = 6.19,2.65 Hz, 1H) 7.91 (br. S., 1H) 7.90 (d, J = 3.79 Hz, 1H) 7.39 (d, J =2.27 Hz, 1H) 7.33 (t, J = 9.60 Hz, 1H) 7.08 (dd, J = 8.97, 2.40 Hz, 1H)7.00 (s, 1H) 6.72 (d, J = 3.54 Hz, 1H) 3.84 (s, 2H) 446.9 19-AB

(MeOD) δ ppm 8.65 (d, J = 1.01 Hz, 1H) 8.36 (d, J = 8.84 Hz, 1H) 8.05(dd, J = 6.32, 2.78 Hz, 1H) 7.93 (d, J = 4.04 Hz, 1H) 7.85-7.95 (m, 1H)7.42 (d, J = 2.02 Hz, 1H) 7.31-7.44 (m, 1H) 7.12 (dd, J = 8.97, 2.40 Hz,1H) 7.04 (d, J = 1.01 Hz, 1H) 6.75 (d, J = 3.79 Hz, 1H) 3.87 (s, 2H)3.65 (d, J = 5.56 Hz, 1H) 3.67 (s, 1H) 2.74 (s, 1H) 2.76 (d, J = 5.56Hz, 1H) 490.9 19-AC

(DMSO-d₆) δ ppm 8.66 (d, J = 1.01 Hz, 1H), 8.29 (d, J = 8.84 Hz, 1H),8.10 (d, J = 3.79 Hz, 1H), 7.96-7.98 (m, 1H), 7.67 (t, J = 6.69 Hz, 1H),7.45-7.50 (m, 2H), 7.14 (dd, J = 8.97, 2.40 Hz, 1H), 7.04 (s, 1H), 6.80(d, J = 3.79 Hz, 1H), 3.73 (s, 2H), 2.30 (s, 3H). 459.9 19-AD

(DMSO-d₆) δ ppm 10.27 (br. S., 1H), 8.65 (d, J = 1.01 Hz, 1H), 8.26 (d,J = 9.09 Hz, 1H), 8.10 (d, J = 3.79 Hz, 1H), 7.94 (t, J = 7.07 Hz, 1H),7.70 (t, J = 7.20 Hz, 1H), 7.47-7.52 (m, 2H), 7.14 (dd, J = 8.84, 2.53Hz, 1H), 7.07 (d, J = 1.01 Hz, 1H), 6.82 (d, J = 4.29 Hz, 1H), 3.80 (s,2H), 2.10 (ddd, J = 6.69, 3.28, 3.16 Hz, 1H), 0.34-0.38 (m, 2H),0.23-0.27 (m, 2H) 485.9 19-AE

(DMSO-d₆) δ ppm 10.35 (br. S., 1H), 8.66 (d, J = 1.0 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.07-8.14 (m, 2H), 7.97-8.05 (m, 1H), 7.51-7.62 (m, 1H),7.49 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 9.0, 2.4 Hz, 1H), 7.09 (d, J =1.0 Hz, 1H), 6.78-6.82 (m, 1H), 5.85-6.19 (m, 1H), 3.81-3.88 (m, 2H),2.85-3.01 (m, 2H), 2.70-2.84 (m, 1H) 510.0 19-AF

(DMSO-d₆) δ ppm 10.39 (s, 1H), 8.65 (d, J = 1.0 Hz, 1H), 8.29 (d, J =8.8 Hz, 1H), 8.06-8.14 (m, 2H), 7.96-8.05 (m, 1H), 7.57 (t, J = 9.7 Hz,1H), 7.48 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 9.0, 2.4 Hz, 1H), 7.10 (s,1H), 6.81 (d, J = 3.3 Hz, 1H), 3.58-3.83 (m, 6H), 3.43 (dd, J = 8.7, 4.2Hz, 1H), 1.86-2.00 (m, 1H), 1.61-1.73 (m, 1H) 516.1 19-AG

(MeOD) δ ppm 8.65 (s, 1H), 8.33 (d, J = 9.09 Hz, 1H), 8.17 (dd, J =6.95, 1.89 Hz, 1H), 7.92 (d, J = 3.79 Hz, 1H), 7.60 (ddd, J = 8.08,4.29, 2.27 Hz, 1H), 7.43 (d, J = 2.02 Hz, 1H), 7.44 (t, J = 9.47 Hz,1H), 7.12 (dd, J = 8.84, 2.27 Hz, 1H), 7.00 (s, 1H), 6.77 (d, J = 3.79Hz, 1H), 3.80 (s, 2H), 2.42 (s, 3H). 459.9 19-AH

(MeOD) δ ppm 8.65 (d, J = 1.01 Hz, 1H) 8.36 (d, J = 9.09 Hz, 1H) 7.93(d, J = 3.54 Hz, 1H) 7.42 (d, J = 2.02 Hz, 2H) 7.34-7.39 (m, 1H) 7.11(s, 1H) 7.13 (d, J = 2.53 Hz, 2H) 6.76 (d, J = 3.54 Hz, 1H) 3.99 (s, 2H)3.63 (d, J = 5.31 Hz, 2H) 3.57 (d, J = 5.81 Hz, 2H) 2.77 (m, 1H) 520.919-AI

(DMSO-d₆) δ ppm 10.39 (br. S., 1H), 8.67 (d, J = 1.0 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.08-8.14 (m, 2H), 7.95-8.04 (m, 1H), 7.57 (t, J = 9.9Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.4 Hz, 1H), 7.10(s, 1H), 6.81 (d, J = 3.5 Hz, 1H), 3.62 (s, 2H), 3.44 (q, J = 4.3 Hz,4H), 2.47 (d, J = 4.8 Hz, 2H), 2.40 (t, J = 4.9 Hz, 2H), 1.98 (s, 3H)557.2 19-AJ

(DMSO-d₆) δ ppm 10.39 (s, 1H), 8.68 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H),8.07-8.14 (m, 2H), 7.95-8.06 (m, 1H), 7.76 (s, 1H), 7.57 (t, J = 9.9 Hz,1H), 7.50 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 9.0, 2.4 Hz, 1H), 7.06 (s,1H), 6.80 (d, J = 3.8 Hz, 1H), 3.66 (s, 2H), 3.16 (t, J = 4.3 Hz, 2H),3.05 (s, 2H), 2.64 (t, J = 5.4 Hz, 2H) 529.1 19-AK

(DMSO-d₆) δ ppm 10.36-10.43 (m, 1H), 8.65 (d, J = 1.0 Hz, 1H), 8.28 (d,J = 9.1 Hz, 1H), 8.09-8.13 (m, 2H), 7.97-8.04 (m, 1H), 7.57 (t, J = 9.7Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 9.0, 2.4 Hz, 1H), 7.04(d, J = 0.8 Hz, 1H), 6.80 (d, J = 3.5 Hz, 1H), 3.60 (s, 3H), 3.56 (s,2H), 2.75-2.83 (m, 2H), 2.30-2.37 (m, 1H), 2.09-2.18 (m, 2H), 1.76-1.85(m, 2H), 1.51-1.63 (m, 2H) 572.2 19-AL

(DMSO-d₆) δ ppm 10.34-10.45 (m, 1H), 8.67 (s, 1H), 8.29 (d, J = 9.1 Hz,1H), 8.13 (d, J = 3.8 Hz, 1H), 8.10 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H),7.65 (t, J = 8.1 Hz, 1H), 7.47-7.53 (m, 2H), 7.09-7.18 (m, 2H), 6.81 (d,J = 3.8 Hz, 1H), 4.54 (t, J = 4.8 Hz, 1H), 4.40-4.47 (m, 1H), 3.83 (s,2H), 2.76-2.92 (m, 2H) 474.0 19-AM

(DMSO-d₆) δ ppm 10.39 (s, 1H), 8.62 (d, J = 1.0 Hz, 1H), 8.28 (d, J =9.1 Hz, 1H), 8.13 (d, J = 3.5 Hz, 1H), 8.10 (d, J = 1.3 Hz, 1H), 7.98(d, J = 8.1 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.46-7.53 (m, 2H), 7.13(dd, J = 9.0, 2.4 Hz, 1H), 7.08 (d, J = 0.8 Hz, 1H), 6.80 (d, J = 3.8Hz, 1H), 4.59 (t, J = 5.7 Hz, 1H), 3.86 (s, 2H), 3.34-3.40 (m, 2H),0.39-0.50 (m, 4H) 498.1 19-AN

(DMSO-d₆) δ ppm 10.40 (s, 1H), 8.66 (d, J = 1.0 Hz, 1H), 8.29 (d, J =9.0 Hz, 1H), 8.13 (d, J = 3.7 Hz, 1H), 8.10 (s, 1H), 7.97 (d, J = 7.8Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.46-7.53 (m, 2H), 7.16 (dd, J = 9.0,2.4 Hz, 1H), 7.04 (s, 1H), 6.80 (d, J = 3.7 Hz, 1H), 4.05 (q, J = 7.1Hz, 2H), 3.56 (s, 2H), 2.79 (d, J = 11.6 Hz, 2H), 2.24-2.32 (m, 1H),2.12 (t, J = 12.1 Hz, 2H), 1.74-1.86 (m, 2H), 1.48-1.63 (m, 2H), 1.16(t, J = 7.1 Hz, 3H) 568.1 19-AO

(DMSO-d₆) δ ppm 10.99 (br. S., 1H) 8.65 (s, 1H) 8.12 (s, 1H) 7.91 (br.M, 1H) 7.66 (t, J = 7.6 Hz, 1H) 7.52 (m, 2H) 7.14 (m, 2H) 6.63 (s, 1H)3.54 (s, 2H) 2.58 (s, 3H) 2.23 (s, 6H) 487.9 19-AP

(DMSO-d₆) δ ppm 10.99 (br. S, 1H) 8.64 (s, 1H) 8.12 (s, 1H) 7.90 (m, 1H)7.66 (t, J = 7.6 Hz, 1H) 7.51 (m, 2H) 7.15-7.18 (m, 2H) 6.62 (s, 1H)3.74 (s, 2H) 2.58 (s, 3H) 2.32 (s, 3H) 473.9 19-AQ

(MeOD) δ ppm 8.61 (d, J = 1.01 Hz, 1H) 8.07 (s, 1H) 7.87 (d, J = 8.84Hz, 1H) 7.55-7.62 (m, 1H), 7.45-7.51 (m, 2H) 7.14 (s, 1H) 7.07 (dd, J =8.72, 7.45 Hz, 1H) 6.53 (s, 1H) 3.92 (s, 2H) 2.61 (d, 3H) 2.19 (m, 1H)0.37-0.51 (m, 4H) 500.2 19-AR

(DMSO-d₆) δ ppm 10.99 (s, 1H) 8.69 (s, 1H) 8.12 (s, 1H) 7.92 (d, J =8.84 Hz, 1H) 7.86 (br. S, 1H) 7.66 (t, J = 7.96 Hz, 1H) 7.52 (d, J =8.84 Hz, 1H) 7.24 (s, 1H) 7.17 (t, J = 8.21 Hz, 1H) 6.62 (s, 1H) 3.81(br. S., 2H) 3.23 (br. S., 2H) 3.17 (s, 2H) 2.77 (br. S., 2H) 2.59 (s,3H) 538.8 19-AS

(DMSO-d₆) δ ppm 10.98 (s, 1H) 8.65 (d, J = 1.01 Hz, 1H) 8.12 (s, 1H)7.90 (d, J = 8.7 Hz,, 1H) 7.66, (t, J = 8.2 Hz, 1H), 7.53 (m, 2H) 7.25(s, 1H) 7.15 (m, 1H) 6.62 (s, 1H) 3.48-3.55 (br. M, 8H) 2.58 (s, 3H)2.40 (m, 2H) 2.00 (s, 3H) 570.9 19-AT

(DMSO-d₆) δ ppm 10.44 (s, 1H), 8.68 (d, J = 1.0 Hz, 1H), 8.29 (d, J =9.1 Hz, 1H), 8.09-8.17 (m, 2H), 7.98-8.06 (m, 1H), 7.58 (t, J = 9.9 Hz,1H), 7.49 (d, J = 2.5 Hz, 1H), 7.10-7.20 (m, 4H), 6.81 (d, J = 3.8 Hz,1H), 3.94 (s, 2H), 3.91 (s, 2H). 526.1 19-AU

(DMSO-d₆) δ ppm 10.39 (s, 1H), 8.65 (d, J = 1.0 Hz, 1H), 8.29 (d, J =9.1 Hz, 1H), 8.13 (d, J = 3.8 Hz, 1H), 8.10 (s, 1H), 7.97 (d, J = 8.1Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.47-7.52(m, 2H), 7.13-7.18 (m, 1H), 7.04 (d, J = 0.8 Hz, 1H), 6.80 (d, J = 3.8Hz, 1H), 3.71-3.88 (m, 1H), 3.55 (s, 2H), 2.85 (d, J = 11.6 Hz, 2H),1.95-2.12 (m, 3H), 1.48-1.70 (m, 4H), 1.01 (d, J = 6.6 Hz, 6H) 581.319-AV

(DMSO-d₆) δ ppm 10.30-10.43 (m, 1H), 8.67 (s, 1H), 8.29 (d, J = 8.8 Hz,1H), 8.13 (d, J = 3.8 Hz, 1H), 8.10 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H),7.65 (t, J = 8.1 Hz, 1H), 7.47-7.54 (m, 2H), 7.15 (dd, J = 8.8, 2.3 Hz,1H), 7.08 (s, 1H), 6.81 (d, J = 3.8 Hz, 1H), 3.80 (s, 2H), 3.22-3.28 (m,2H), 2.99 (s, 3H), 2.95 (t, J = 6.7 Hz, 2H) 534.0 19-AW

(DMSO-d₆) δ ppm 10.96 (br. S, 1H) 8.64 (d, J = 1.01 Hz, 1H) 8.13 (dd, J= 6.57, 2.53 Hz, 1H) 7.96 (dd, J = 4.67, 3.41 Hz, 1H) 7.59 (t, J = 9.73Hz, 1H) 7.53 (d, J = 8.84 Hz, 1H) 7.19 (s, 1H) 7.16 (dd, J = 8.84, 7.58Hz, 1H) 6.62 (s, 1H) 3.75 (s, 2H) 2.58 (s, 3H) 2.32 (s, 3H). 492.1 19-AX

(MeOD) δ ppm 8.63 (s, 1H) 8.40 (dd, J = 7.07, 2.02 Hz, 1H) 7.62 (s, 2H)7.47 (d, J = 10.11 Hz, 1H) 7.11-7.13 (m, 1H) 7.09 (d, J = 1.26 Hz, 1H)6.55 (s, 1H) 3.84 (s, 2H) 2.65 (s, 3H) 2.44 (s, 3H) 492.4 19-AY

(DMSO-d₆) δ ppm 8.67 (s, 1H) 8.16 (d, J = 8.84 Hz, 1H) 8.07 (s, 1H) 7.97(d, J = 3.79 Hz, 1H) 7.90 (d, J = 8.34 Hz, 1H) 7.58 (t, J = 7.96 Hz, 1H)7.46 (d, J = 7.83 Hz, 1H) 7.14-7.30 (m, 2H) 6.84 (d, J = 3.79 Hz, 1H)4.03 (s, 2H) 2.58 (s, 3H). 460.0 19-AZ

(DMSO-d₆) δ ppm 10.39 (s, 1H), 8.65 (s, 1H), 8.28 (d, J = 9.1 Hz, 1H),8.08-8.14 (m, 2H), 7.95-8.05 (m, 2H), 7.57 (t, J = 9.9 Hz, 1H), 7.49 (d,J = 2.5 Hz, 1H), 7.15 (dd, J = 9.0, 2.4 Hz, 1H), 7.10 (s, 1H), 6.80 (d,J = 3.5 Hz, 1H), 4.09-4.22 (m, 1H), 3.62-3.77 (m, 2H), 2.67-2.77 (m,2H), 2.39-2.48 (m, 2H), 2.02-2.16 (m, 1H), 1.77 (s, 3H), 1.50-1.64 (m,1H) 557.2

EXAMPLE 20 20-A.5-(6-Methoxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

To a solution of5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (230 mg, 0.46 mmol) is added 1 mLmethanol followed by sodium hydride (100 mg, 60% in mineral oil) isadded portions over 5 min. The mixture is stirred at rt for 0.5 h andthen poured into water, extracted with EtOAc. The extract is dried,filtered, and concentrated under reduced pressure. The residue ispurified by FCC (MeOH with 1% NH₄OH/DCM from 0% to 5%) to give the titlecompound.

MS (ESI) m/z 443.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.63 (s, 1H),8.36 (d, J=8.84 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J=3.79 Hz, 1H), 7.90 (d,J=8.08 Hz, 1H), 7.58 (t, J=7.83 Hz, 1H), 7.43 (d, J=2.27 Hz, 2H), 7.12(dd, J=8.97, 2.40 Hz, 1H), 7.00 (d, J=1.01 Hz, 1H), 6.76 (d, J=3.79 Hz,1H), 4.50 (s, 2 H) 3.46 (s, 3H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 20-B

(MeOD) δ ppm 8.61 (d, J = 1.01 Hz, 1H), 8.36 (d, J = 8.84 Hz, 1H), 8.06(s, 1H), 7.95 (d, J = 3.54 Hz, 1H), 7.90 (d, J = 8.34 Hz, 1H), 7.57 (t,J = 7.96 Hz, 1H), 7.42 (d, J = 2.27 Hz, 2H), 7.12 (dd, J = 8.97, 2.40Hz, 1H), 7.04 (s, 1H), 6.75 (d, J = 3.79 Hz, 1H), 4.55 (s, 2H), 3.73(quin, J = 6.06 Hz, 1H), 1.20 (d, J = 6.06 Hz, 6H). 471.1 20-C

(DMSO-d₆) δ ppm 10.40 (s, 1H), 8.69 (d, J = 1.01 Hz, 1H), 8.29 (d, J =8.84 Hz, 1H), 8.10-8.12 (m, 2H), 7.98-8.03 (m, 1H), 7.55-7.58 (m, 1H),7.51 (d, J = 2.27 Hz, 1H), 7.16 (dd, J = 8.97, 2.40 Hz, 1H), 6.94 (d, J= 1.01 Hz, 1H), 6.82 (d, J = 3.79 Hz, 1H), 4.48 (s, 2H), 3.39 (s, 3H).460.9 20-D

(DMSO-d₆) δ ppm 10.28 (s, 1H), 8.69 (d, J = 1.01 Hz, 1H), 8.27 (d, J =9.09 Hz, 1H), 8.11 (d, J = 3.79 Hz, 1H), 7.94 (m, 1H), 7.71 (t, J = 7.20Hz, 1H), 7.47-7.52 (m, 2H), 7.16 (dd, J = 8.97, 2.40 Hz, 1H), 6.93 (d, J= 1.01 Hz, 1H), 6.82 (d, J = 3.79 Hz, 1H), 4.48 (s, 2H), 3.39 (s, 3H).460.9

EXAMPLE 215-[6-(Acetylamino-methyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (50 mg, 0.12 mmol) and THF (5 mL)is added acetyl chloride (50 mg) and triethylamine (50 mg). The solutionis stirred at rt for 10 min before being partitioned between EtOAc andwater. The organic layer is washed further with brine. The organic layeris then dried (Na₂SO₄), filtered, and concentrated under reducedpressure to give the title compound. MS (ESI) m/z 470.0 (M+1); ¹H NMR(400 MHz, MeOD) δ ppm 8.61 (d, J=1.01 Hz, 1H), 8.34 (d, J=9.09 Hz, 1H),8.05 (s, 1H), 7.93 (d, J=3.54 Hz, 1H), 7.89 (d, J=7.83 Hz, 1H), 7.56 (t,J=7.96 Hz, 1H), 7.39-7.45 (m, 2H), 7.09 (dd, J=8.97, 2.40 Hz, 1H), 6.88(s, 1H), 6.73 (d, J=3.79 Hz, 1H), 4.40 (s, 2H) 2.01 (s, 3H).

EXAMPLE 225-[6-(3,3-Dimethyl-ureidomethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (50 mg, 0.12 mmol), THF (5 mL),and dimethylcarbamyl chloride (50 mg) is added triethylamine (50 mg).After 10 min the solution is partitioned between EtOAc and water. Theorganic layer is separated and washed further with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to give thetitle compound.

MS (ESI) m/z 499.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.60 (s, 1H),8.34 (d, J=9.09 Hz, 1H), 8.06 (s, 1H), 7.86-7.95 (m, 2H), 7.56 (t,J=7.96 Hz, 1H), 7.38-7.46 (m, 2H), 7.09 (dd, J=9.09, 2.27 Hz, 1H), 6.83(d, J=1.01 Hz, 1H), 6.73 (d, J=3.79 Hz, 1H), 4.36 (s, 2H), 2.89 (s, 6H).

EXAMPLE 235-[6-(Methanesulfonylamino-methyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (100 mg, 0.23 mmol) and THF (5 mL)is added methanesulfonic anhydride (87 mg, 0.5 mmol) and pyridine (0.2mL). After 0.5 h the solution is partitioned between EtOAc and water.The organic layer is washed further with brine, dried over sodiumsulfate, and concentrated under reduced pressure. The residue isseparated by FCC (EtOAc/heptane from 10 to 100%) to give the titlecompound.

MS (ESI) m/z 505.8 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.64 (d, J=1.01Hz, 1H), 8.36 (d, J=9.09 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J=3.79 Hz, 1H),7.90 (d, J=8.34 Hz, 1H), 7.58 (t, J=8.08 Hz, 1H), 7.43 (d, J=2.53 Hz,1H), 7.45 (s, 1H), 7.12 (dd, J=8.97, 2.40 Hz, 1H), 7.10 (d, J=1.01 Hz,1H), 6.75 (d, J=3.79 Hz, 1H), 4.34 (s, 2H), 2.99 (s, 3H).

EXAMPLE 24 24-A. 5-(2-Chloro-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

To a precooled (−78° C.) solution of 2,2,6,6-tetramethylpiperidine (0.79mL, 4.71 mmol) in THF (10 mL) is added n-butyllithium (1.76 mL, 2.5 M).After 10 min a solution of 5-(2-Chloro-pyrimidin-4-yloxy)-1H-indole,prepared as in WO2006/034833, (0.771 g, 3.32 mmol) in THF (10 mL) isadded. After an additional 15 min 3-(trifluoromethyl)-phenyl isocyanate(0.88 mL, 6.28 mmol) is added. The solution is then allowed to warmgradually to rt. After 1 h the solution is concentrated and the residuetaken up in EtOAc and washed with brine. The title compound is isolatedvia flash chromatography (10-30% EtOAc/heptane).

MS (ESI) m/z 433.0 & 434.9 (M+1).

24-B. 5-(2-Methyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

To a solution of 5-(2-Chloro-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (Example 24-A, 0.150 g, 0.347 mmol),Pd(tBu₃P)₂ (0.009 g, 0.017 mmol) and THF (5 mL) is added MeZnCl (0.35mL, 2.0 M THF) under an argon atmosphere

The solution is then heated to reflux for 2 h. After cooling to rt theTHF is removed in vacuo and the residue is separated by flashchromatography (30-75% EtOAc/heptane) followed by additional separationvia semi-prep HPLC to give the title compound

MS (ESI) m/z 413.1 (M+1);

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.38 (s, 1H), 8.54 (d, J=5.6 Hz, 1H),8.29 (d, J=8.8 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 8.10 (s, 1H), 7.97 (d,J=7.8 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.48 (d, J=2.3 Hz,1H), 7.14 (dd, J=9.0, 2.4 Hz, 1H), 6.84 (d, J=5.8 Hz, 1H), 6.81 (d,J=3.5 Hz, 1H), 2.43 (s, 3H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 24-C

(DMSO-d₆) δ ppm 10.4 (s, 1H), 8.57 (d, J = 5.8 Hz, 1H), 8.29 (d, J = 9.1Hz, 1H), 8.13 (d, J = 3.5 Hz, 1H), 8.10 (s, 1H), 7.97 (d, J = 8.6 Hz,1H), 7.65 (t, J = 8.0 Hz, 1H), 7.47-7.54 (m, 1H), 7.48 (d, J = 2.5 Hz,1H), 7.14 (dd, J = 9.0, 2.4 Hz, 1H), 6.83 (d, J = 5.8 Hz, 1H), 6.80 (d,J = 3.8 Hz, 1H), 2.56 (d, J = 7.1 Hz, 2H), 2.00-2.13 (m, 1H), 0.84 (d, J= 6.8 Hz, 6H) 455.1 24-D

(DMSO-d₆) δ ppm 10.38 (s, 1H), 8.56 (d, J = 5.8 Hz, 1H), 8.28 (d, J =8.8 Hz, 1H), 8.13 (d, J = 3.5 Hz, 1H), 8.10 (s, 1H), 7.98 (d, J = 8.1Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.14 (dd, J= 9.0, 2.4 Hz, 1H), 6.82 (d, J = 5.8 Hz, 1H), 6.80 (d, J = 3.5 Hz, 1H),2.57 (d, J = 7.3 Hz, 2H), 1.70-1.83 (m, 1H), 1.52-1.65 (m, 6H),1.08-1.19 (m, 2H), 0.86-0.98 (m, 2H) 495.2 24-E

(CDCl₃) δ ppm 8.69 (d, J = 0.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.86(s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 3.8 Hz, 1H), 7.50-7.58(m, 2H), 7.44-7.49 (m, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 8.9,2.3 Hz, 1H), 6.76 (s, 1H), 6.72 (d, J = 3.4 Hz, 1H), 2.52 (s, 3H) 413.124-F

(DMSO-d₆) δ ppm 10.38 (s, 1H), 8.64 (d, J = 1.0 Hz, 1H), 8.28 (d, J =9.0 Hz, 1H), 8.13 (d, J = 3.7 Hz, 1H), 8.10 (s, 1H), 7.97 (d, J = 8.6Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.47-7.53 (m, 2H), 7.14 (dd, J = 9.0,2.4 Hz, 1H), 6.94 (d, J = 0.9 Hz, 1H), 6.80 (d, J = 3.4 Hz, 1H), 2.57(d, J = 7.1 Hz, 2H), 2.00-2.18 (m, 1H), 0.90 (d, J = 6.7 Hz, 6H) 455.1

EXAMPLE 25 5-(2-Hydroxymethyl-pyridin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethylphenyl)-amide 25-A. 4-Chloro-pyridine-2-carboxylicacid tert-butyl ester

4-Chloro-pyridine-2-carbonyl chloride•hydrochloride (ref. Org. Proc.Res. Dev. 2002, 6, 777) (17.0 g, 81.3 mmol) is taken up in THF (200 mL)and sodium tert-butoxide (23.4 g, 243.5 mmol) is added in portions.After 1.5 h the mixture is diluted with water (500 mL) and extractedwith EtOAc (2×500 mL). The combined organic layers are dried (Na₂SO₄),filtered and then concentrated. The residue is then separated via FCC(10-30% EtOAc/heptane) to give the title compound. MS (ESI) m/z 213.9 &215.9 (M+1)

25-B. 4-(1H-Indol-5-yloxy)-pyridine-2-carboxylic acid tert-butyl ester

5-Hydroxyindole (100 mg, 0.72 mmol), 4-Chloro-pyridine-2-carboxylic acidtert-butyl ester (160 mg, 0.72 mmol) and cesium carbonate (245 mg, 0.72mmol) are combined in DMSO (1.5 mL) and heated at 105° C. for 3 h in asealed tube. The reaction is cooled to rt and partitioned between EtOAcand brine. The organic layer is removed, dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue is separated via FCC(EtOAc/heptanes 2:8 to EtOAc) to give the title compound. MS (ESI) m/z311.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.29 (br. S., 1H), 8.50(d, J=5.8 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.46 (t, J=2.8 Hz, 1H), 7.37(m, 2H), 7.07 (dd, J=5.6, 2.5 Hz, 1H), 6.91 (dd, J=8.6, 2.3 Hz, 1H),6.47 (t, J=2.1 Hz, 1H), 1.51 (s, 9H).

25-C.4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester

A solution of n-butyllithium (0.75 mL, 1.20 mmol, 1.6M in hexanes) isadded to a precooled (−78° C.) solution of 2,2,6,6-tetramethylpiperidine(0.22 mL, 1.30 mmol) and THF (5 mL). After 15 min a THF solution (2 mL)of 4-(1H-indol-5-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (310mg, 1.00 mmol) is added. After an additional 0.5 h3-trifluoromethylphenyl isocyanate (0.27 mL, 2.00 mmol) is added.Reaction is then allowed to warm to rt and stir for 3 h. At that pointthe reaction is partitioned between EtOAc and pH 7 buffer solution.Organic removed and dried over anhydrous Na₂SO₄. Following concentrationthe residue is separated via FCC (EtOAc/heptanes 1:9 to EtOAc/heptanes7:3) to give the title compound. MS (ESI) m/z 498.2 (M+1); ¹H NMR (400MHz, CD₂Cl₂) δ ppm 8.41-8.47 (m, 1H), 8.37 (s, 1H), 8.34 (d, J=9.1 Hz,1H), 7.97 (s, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.73 (d, J=3.5 Hz, 1H), 7.63(d, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.46-7.51 (m, 1H), 7.38 (d, 1H), 7.13(dd, J=9.0, 2.4 Hz, 1H), 6.92 (dd, J=5.6, 2.5 Hz, 1H), 6.69 (d, J=3.8Hz, 1H), 1.60 (s, 9H).

25-D. 5-(2-Hydroxymethyl-pyridin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethylphenyl)-amide

Dissolve4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester (400 mg, 0.80 mmol) in THF (10 mL) at 0° C. beforeadding lithium aluminum hydride (2.4 mL, 2.40 mmol, 1.0M ethersolution). The reaction is allowed to warm to room temperature for 3 hbefore quenching it and extracting between EtOAc and saturated aqueousNH₄Cl. Organic is dried over anhydrous Na₂SO₄ and purified via FCC(EtOAc/heptanes 3:7 to EtOAc) to give the title compound as a whitesolid (182 mg, 53%). MS (ESI) m/z 428.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.39 (s, 1H), 8.29-8.37 (m, 2H), 8.15 (d, J=3.8 Hz, 1H), 8.09 (s,1H), 7.98 (d, J=8.5 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.50 (d, J=7.7 Hz,1H), 7.47 (d, J=2.4 Hz, 1H), 7.13 (dd, J=8.9, 2.5 Hz, 1H), 6.92 (d,J=2.4 Hz, 1H), 6.77-6.85 (m, 2H), 5.35 (t, J=5.8 Hz, 1H), 4.49 (d, J=5.8Hz, 2H).

EXAMPLE 26 26-A. Methanesulfonic acid4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]pyridin-2-ylmethylester

Methansulfonyl chloride (0.2 mL, 2.46 mmol) is added to a solution of5-(2-hydroxymethyl-pyridin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethylphenyl)-amide, Example 25-D, (700 mg, 1.64 mmol) andtriethylamine (0.7 mL, 4.92 mmol) in DCM (50 mL) at rt. After 1 h thereaction is partitioned between DCM and saturated aqueous NaHCO₃.Organic layer is removed, dried over anhydrous Na₂SO₄, concentrated andthen separated via FCC (EtOAc/heptanes 2:4 to EtOAc/heptanes 9:1) togive the title compound. MS (ESI) m/z 506.0 (M+1).

26-B. 5-[2-(Isopropylamino-methyl)-pyridin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

A solution of methanesulfonic acid4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]pyridine-2-ylmethylester (150 mg, 0.30 mmol) and isopropyl amine (5 mL) is stirred at Itfor 2 h. The reaction is concentrated under reduced pressure and theresidue separated via semi-prep HPLC (C18; 10-100% I/H₂O with 0.1%NH₄OH) to give5-[2-(isopropylamino-methyl)-pyridin-4-yloxy]-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 469.2 (M+1); ¹H NMR (400MHz, MeOD) δ ppm 8.25-8.37 (m, 2H), 7.97 (s, 1H), 7.88 (d, J=3.8 Hz,1H), 7.80 (d, J=8.1 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.6 Hz,1H), 7.30 (d, J=2.3 Hz, 1H), 7.00 (dd, J=9.0, 2.4 Hz, 1H), 6.90 (d,J=2.3 Hz, 1H), 6.81 (dd, J=5.8, 2.3 Hz, 1H), 6.66 (d, J=3.8 Hz, 1H),4.01 (s, 2H), 3.09-3.18 (m, 1H), 1.18 (d, J=6.6 Hz, 6H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 26-C

(MeOD) δ ppm 8.23-8.33 (m, 2 H), 7.97 (s, 1 H), 7.87 (d, J = 3.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1 H), 7.48 (t, J = 8.1 Hz, 1 H), 7.35 (d, J =7.8 Hz, 1 H), 7.30 (d, J = 2.3 Hz, 1 H), 7.00 (dd, J = 9.0, 2.4 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1 H), 6.78 (dd, J = 5.8, 2.3 Hz, 1 H), 6.66 (d,J = 3.5 Hz, 1 H), 3.99 (s, 2 H), 2.28- 2.38 (m, 1 H), 0.44-0.59 (m, 4H). 467.2 26-D

(MeOD) δ ppm 8.24-8.33 (m, 2 H), 7.97 (s, 1 H), 7.87 (d, J = 3.8 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.35 (d, J =7.8 Hz, 1 H), 7.30 (d, J = 2.3 Hz, 1 H), 7.00 (dd, J = 9.0, 2.4 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1 H), 6.75 (dd, J = 5.8, 2.3 Hz, 1 H), 6.66 (d,J = 3.8 Hz, 1 H), 3.73 (s, 2 H), 2.33 (s, 3 H). 441.2 26-E

(MeOD) δ ppm 8.28 (d, J = 8.8 Hz, 1 H), 8.21 (d, J = 5.8 Hz, 1 H), 7.97(s, 1 H), 7.87 (d, J = 3.8 Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1 H),7.48 (t,J = 8.1 Hz, 1 H), 7.35 (d, J = 7.3 Hz, 1 H), 7.29 (d, J = 2.3 Hz, 1 H),6.95-7.03 (m, 2 H), 6.75 (dd, J = 5.8, 2.5 Hz, 1 H), 6.66 (d, J = 3.8Hz, 1 H), 3.52-3.58 (m, 4 H), 3.47 (s, 2 H), 2.31-2.41 (m, 4 H). 497.326-F

(MeOD) δ ppm 8.22-8.23 (m, 2 H), 7.97 (s, 1 H), 7.87 (d, J = 3.5 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.35 (d, J =8.6 Hz, 1 H), 7.29 (d, J = 2.3 Hz, 1 H), 7.00 (dd, J = 9.0, 2.4 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1 H), 6.76 (dd, J = 5.8, 2.5 Hz, 1 H), 6.66 (d,J = 3.5 Hz, 1 H), 3.78-3.88 (m, 4 H), 3.24-3.32 (m, 2 H), 2.59- 2.74 (m,1 H), 1.68-1.82 (m, 2 H), 1.26-1.41 (m, 2 H). 511.2 26-G

(MeOD) δ ppm 8.21-8.33 (m, 2 H), 7.97 (s, 1 H), 7.87 (d, J = 3.8 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1 H), 7.49 (t, J = 8.1 Hz, 1 H), 7.35 (d, J =7.8 Hz, 1 H), 7.30 (d, J = 2.3 Hz, 1 H), 7.00 (dd, J = 9.0, 2.4 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1 H), 6.74 (dd, J = 5.8, 2.5 Hz, 1 H), 6.66 (d,J = 3.8 Hz, 1 H), 3.75 (s, 2 H), 3.55 (t, J = 5.6 Hz, 2 H), 2.63 (t, J =5.6 Hz, 2 H). 471.3 26-H

(MeOD) δ ppm 8.16-8.32 (m, 2 H), 7.95 (dd, J = 6.3, 2.8 Hz, 1 H),7.77-7.87 (m, 2 H), 7.18-7.32 (m, 2 H), 6.99 (dd, J = 8.8, 2.3 Hz, 1 H),6.89 (d, J = 2.3 Hz, 1 H), 6.73 (dd, J = 5.8, 2.3 Hz, 1 H), 6.65 (d, J =3.5 Hz, 1 H), 3.67 (s, 2 H), 2.29 (s, 3 H). 459.1

EXAMPLE 27 27-A.6-Tetrazol-2-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide

To a solution of 1H-tetrazole (48 mg, 0.68 mmol) in DMF (3 mL), NaH (27mg, 0.68 mmol) is added at 0° C. After 30 min, methanesulfonic acid6-[1-(4-fluoro-3-trifluoromethyl-phenylcarbamoyl)-1H-indol5-yloxy]-pyrimidin-4-ylmethyl ester (300 mg, 0.57 mmol) is added and thereaction is allowed to reach rt and then stir overnight. A saturatedsolution of ammonium chloride is added (2 mL) followed by EtOAc (4 mL).The layers are separated and the aqueous layer is extracted further withEtOAc (3×). The combined organics are evaporated and dried to give thecrude product. The residue is purified using silica gel columnchromatography FCC (gradient elution: 100% DCM to 98% DCM 2% MeOH) togive the titled compound. MS (ESI) m/z 499.1 (M+1);

¹H NMR (400 MHz, MeOD) δ ppm 8.78 (s, 1H) 8.63 (d, J=1.01 Hz, 1H) 8.35(d, J=9.09 Hz, 1H) 8.05 (dd, J=6.06, 2.53 Hz, 1H) 7.93 (d, J=3.79 Hz,2H) 7.42 (d, J=2.27 Hz, 1H) 7.36 (t, J=9.60 Hz, 1H) 7.11 (dd, J=9.09,2.53 Hz, 1H) 6.88 (s, 1H) 6.75 (d, J=3.79 Hz, 1H) 6.03 (s, 2H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 27-B

(MeOD) δ ppm 9.33 (s, 1 H) 8.62 (d, J = 1.01 Hz, 1 H) 8.34 (d, J = 8.84Hz, 1 H) 8.04 (dd, J = 6.32, 2.78 Hz, 1 H) 7.92 (d, J = 3.79 Hz, 2 H)7.41 (d, J = 2.27 Hz, 1 H) 7.35 (t, J = 9.60 Hz, 1 H) 7.10 (dd, J =8.97, 2.40 Hz, 1 H) 6.97 (s, 1 H) 6.74 (d, J = 3.79 Hz, 1 H) 5.82 (s, 2H) 499.1 27-C

(MeOD) δ ppm 8.53 (d, J = 1.01 Hz, 1 H) 8.22 (d, J = 9.09 Hz, 1 H) 7.94(dd, J = 6.19, 2.65 Hz, 1 H) 7.79-7.84 (m, 2 H) 7.22- 7.28 (m, 2 H) 6.96(dd, J = 8.84, 2.27 Hz, 1 H) 6.61 (m, 2 H) 6.34 (s, 1 H) 5.04 (s, 2 H)2.17 (s, 3 H) 1.91 (s, 3 H) 525.9 27-D

(DMSO-d₆) δ ppm 10.39 (s, 1 H), 8.58- 8.77 (m, 2 H), 8.23-8.32 (m, 1 H),8.07- 8.15 (m, 2 H), 7.96-8.05 (m, 2 H), 7.57 (t, J = 9.7 Hz, 1 H), 7.49(d, J = 2.3 Hz, 1 H), 7.14 (dd, J = 9.0, 2.4 Hz, 1 H), 6.87 (d, J = 1.0Hz, 1 H), 6.80 (d, J = 3.5 Hz, 1 H), 5.56 (s, 2 H) 498.0 27-E

(MeOD) δ ppm 8.64 (d, J = 1.01 Hz, 1 H), 8.30 (d, J = 8.84 Hz, 1 H),8.17 (dd, J = 7.07, 2.02 Hz, 1 H), 7.91 (d, J = 3.54 Hz, 1 H), 7.80 (d,J = 2.53 Hz, 1 H), 7.56 (d, J = 1.77 Hz, 1 H), 7.56-7.62 (m, 1 H), 7.44(t, J = 9.35 Hz, 1 H), 7.37 (d, J = 2.27 Hz, 1 H), 7.07 (dd, J = 8.97,2.40 Hz, 1 H), 6.75 (d, J = 3.79 Hz, 1 H), 6.37 (t, J = 2.15 Hz, 1 H),6.39 (s, 1 H), 5.45 (s, 2 H). 496.9 27-F

(MeOD) δ ppm 8.66 (s, 1 H), 8.31 (d, J = 9.09 Hz, 1 H), 8.17 (dd, J =6.95, 2.15 Hz, 1 H), 7.92 (d, J = 3.79 Hz, 1 H), 7.80 (s, 1 H), 7.60 (m,1 H), 7.40 (d, J = 2.53 Hz, 1 H), 7.45 (t, J = 9.35 Hz, 1 H), 7.20- 7.21(m, 1 H), 7.09 (dd, J = 9.09, 2.27 Hz, 1 H), 7.02 (s, 1 H), 6.75 (d, J =3.79 Hz, 1 H), 6.63 (s, 1 H), 5.33 (s, 2 H). 496.9 27-G

(DMSO-d₆) δ ppm 10.39 (br. S., 1 H), 8.70 (d, J = 1.0 Hz, 1 H), 8.27 (d,J = 8.8 Hz, 1 H), 8.08-8.14 (m, 2 H), 7.95-8.04 (m, 1 H), 7.57 (t, J =9.7 Hz, 1 H), 7.47 (d, J = 2.5 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1H), 6.79 (d, J = 3.5 Hz, 1 H), 6.66 (d, J = 1.3 Hz, 1 H), 6.50 (d, J =0.8 Hz, 1 H), 6.44 (d, J = 1.5 Hz, 1 H), 5.37-5.46 (m, 2 H), 5.05 (s, 2H) 512.0 27-H

(Acetone-d₆) δ ppm 10.66 (s, 1 H) 9.19 (s, 1 H) 8.98 (d, J = 9.09 Hz, 1H) 8.80 (dd, J = 6.32, 2.53 Hz, 1 H) 8.76 (d, J = 3.79 Hz, 1 H) 8.68(dd, J = 8.84, 3.79 Hz, 1 H) 8.03 (d, J = 2.27 Hz, 1 H) 7.99 (t, J =9.73 Hz, 1 H) 7.73 (dd, J = 8.97, 2.40 Hz, 1 H) 7.63 (s, 1 H) 7.30 (d, J= 3.79 Hz, 1 H) 6.37 (s, 2 H) 3.20 (s, 3 H). 513.9 27-I

(Acetone-d₆) δ ppm 10.67 (s, 1 H) 9.24 (s, 1 H) 9.01 (d, J = 9.09 Hz, 1H) 8.83 (dd, J = 6.32, 2.53 Hz, 1 H) 8.78 (d, J = 3.79 Hz, 1 H) 8.72(dd, J = 8.08, 3.79 Hz, 1 H) 8.01- 8.07 (m, 1 H) 8.06 (d, J = 2.02 Hz, 1H) 7.76 (dd, J = 8.97, 2.40 Hz, 1 H) 7.51 (s, 1 H) 7.34 (d, J = 3.54 Hz,1 H) 6.57 (s, 2 H) 3.09 (s, 3 H). 513.9 27-J

(DMSO-d₆) δ ppm 10.38 (br. S., 1 H), 8.70 (d, J = 1.0 Hz, 1 H), 8.29 (d,J = 9.1 Hz, 1 H), 8.06-8.17 (m, 2 H), 7.96-8.05 (m, 1 H), 8.57 (t, J =9.9 Hz, 1 H), 7.50 (d, J = 2.5 Hz, 1 H), 7.15 (dd, J = 9.0, 2.4 Hz, 1H), 6.77-6.88 (m, 4 H), 5.50 (s, 2 H) 514.0 27-K

(DMSO-d₆) δ ppm 10.40 (s, 1 H), 8.70 (d, J = 1.0 Hz, 1 H), 8.28 (d, J =9.1 Hz, 1 H), 8.11 (d, J = 3.8 Hz, 2 H), 7.95-8.06 (m, 1 H), 7.57 (t, J= 9.9 Hz, 1 H), 7.51 (d, J = 2.3 Hz, 1 H), 7.16 (dd, J = 9.0, 2.4 Hz, 1H), 7.00 (s, 1 H), 6.81 (d, J = 3.3 Hz, 1 H), 6.08 (d, J = 5.3 Hz, 1 H),5.76 (s, 2 H) 514.0 27-L

(DMSO-d₆) δ ppm 8.69 (d, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 8.13 (d, J =3.8 Hz, 1 H), 8.08-8.11 (m, 1 H), 7.95-8.00 (m, 1 H), 7.88 (s, 2 H),7.65 (t, J = 8.0 Hz, 1 H), 7.47- 7.54 (m, 2 H), 7.14 (dd, J = 9.0, 2.4Hz, 1 H), 6.80 (d, J = 3.5 Hz, 1 H), 6.70 (d, J = 0.8 Hz, 1 H), 5.80 (s,2 H) 480.0 27-M

(DMSO-d₆) δ ppm 10.39 (s, 1 H), 8.70 (d, J = 1.0 Hz, 1 H), 8.28 (d, J =9.1 Hz, 1 H), 8.25 (d, J = 0.8 Hz, 1 H), 8.13 (d, J = 3.8 Hz, 1 H),8.08-8.11 (m, 1 H), 7.95-8.01 (m, 1 H), 7.80 (d, J = 1.0 Hz, 1 H), 7.65(t, J = 8.0 Hz, 1 H), 7.47-7.53 (m, 2 H), 7.15 (dd, J = 9.0, 2.4 Hz, 1H), 6.87 (d, J = 0.8 Hz, 1 H), 6.81 (d, J = 3.5 Hz, 1 H), 5.77 (s, 2 H)480.0 27-N

(MeOD) δ ppm 8.62 (d, J = 1.01 Hz, 1 H) 8.32 (d, J = 9.09 Hz, 1 H), 8.05(dd, J = 6.19, 2.65 Hz, 1 H), 7.90-7.95 (m, 2 H) 7.34- 7.39 (m, 2 H)7.22 (d, J = 2.53 Hz, 1 H) 7.05 (dd, J = 8.97, 2.40 Hz, 1 H) 6.94 (s, 1H) 6.73 (d, J = 3.79 Hz, 1 H) 5.46 (d, J = 2.27 Hz, 1 H) 4.37 (s, 2 H)3.63 (s, 3 H) 526.9

EXAMPLE 28 28-A.4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylicacid

A solution of4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester (1 g, 2.01 mmol) and TFA (20 mL) is stirred at rtfor 2 h. The reaction is concentrated in vacuo and used without furtherpurification in the next step. MS (ESI) m/z 442.0 (M+1).

28-B. 5-(2-Methylcarbamoyl-pyridin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

A mixture of4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylicacid (150 mg, 0.27 mmol), DCM (3 mL), and triethylamine (0.11 mL, 0.81mmol) is stirred at 0° C. and oxalyl chloride (0.27 mL, 0.54 mmol, 2.0 MDCM solution) is added. After 30 min, excess methylamine (2.0M DCMsolution) is added. After an additional 30 min, the reaction ispartitioned between DCM and saturated aqueous NaHCO₃.

Organic layer is removed and dried over anhydrous Na₂SO₄. Followingconcentration the residue is separated via semi-prep HPLC (C18; 10-100%I/H₂O with 0.1% NH₄OH) to give the title compound.

MS (ESI) m/z 455.2 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.36 (d, J=5.6Hz, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=3.8 Hz, 1H),7.81 (d, J=8.3 Hz, 1H), 7.47-7.52 (m, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.35(d, J=7.8 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.01 (dd, J=9.0, 2.4 Hz, 1H),6.96 (dd, J=5.6, 2.5 Hz, 1H), 6.66 (d, J=3.8 Hz, 1H), 2.83 (s, 3H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 28-C

(MeOD) δ ppm 8.42 (d, J = 5.6 Hz, 1 H), 8.31 (d, J = 9.1 Hz, 1 H), 7.97(s, 1 H), 7.87 (d, J = 3.8 Hz, 1 H), 7.81 (d, J = 8.3 Hz, 1 H), 7.56 (d,J = 2.3 Hz, 1 H), 7.48 (t, J = 8.1 Hz, 1 H), 7.40 (d, J = 2.3 Hz, 1 H),7.30-7.38 (m, 2 H), 6.98-7.06 (m, 2 H), 6.67 (d, J = 3.8 Hz, 1 H), 6.55(d, J = 2.5 Hz, 1 H), 3.73 (s, 3 H). 521.1 28-D

(MeOD) δ ppm 8.36 (d, J = 5.6 Hz, 1 H), 8.29 (d, J = 9.1 Hz, 1 H), 7.97(s, 1 H), 7.86 (d, J = 3.8 Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1 H),7.43-7.52 (m, 2 H), 7.27-7.38 (m, 2 H), 6.93-7.04 (m, 2 H), 6.66 (d, J =3.5 Hz, 1 H), 3.46 (t, J = 6.7 Hz, 2 H), 2.64 (t, J = 6.7 Hz, 2 H), 2.54(br. s., 4H), 1.64-1.77 (m, 4 H). 538.2 28-E

(DMSO-d₆) δ ppm 10.42 (s, 1 H), 8.51 (d, J = 5.6 Hz, 1 H), 8.35 (d, J =8.8 Hz, 1 H), 8.17 (d, J = 3.8 Hz, 1 H), 8.10 (s, 2 H), 7.98 (d, J = 8.3Hz, 1 H), 7.59-7.73 (m, 2 H), 7.45-7.58 (m, 2 H), 7.38 (d, J = 2.5 Hz, 1H), 7.11-7.25 (m, 2 H), 6.83 (d, J = 3.5 Hz, 1H). 441.0 28-F

(DMSO-d₆) δ ppm 10.42 (s, 1 H), 8.72 (d, J = 5.1 Hz, 1 H), 8.49 (d, J =5.6 Hz, 1 H), 8.34 (d, J = 8.8 Hz, 1 H), 8.17 (d, J = 3.8 Hz, 1 H), 8.10(s, 1 H), 7.98 (d, J = 8.1 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H),7.45-7.54 (m, 2 H), 7.37 (d, J = 2.5 Hz, 1 H), 7.12-7.23 (m, 2 H), 6.83(d, J = 3.5 Hz, 1 H), 2.79-2.90 (m, 1 H), 0.66 (d, J = 9.3 Hz, 4 H)481.0 28-G

(DMSO-d₆) δ ppm 10.44 (br. S., 1 H), 8.41- 8.54 (m, 3 H), 8.16 (d, J =3.8 Hz, 1 H), 8.07 (s, 1 H), 7.87 (br. S., 1 H), 7.54 (br. S., 1 H),7.46 (br. S., 1 H), 7.26-7.41 (m, 2 H), 7.17 (dd, J = 6.2, 1.6 Hz, 1 H),7.06- 7.14 (m, 1 H), 6.71 (br. S., 1 H), 4.00- 4.11 (m, 1 H), 1.16 (d, J= 6.6 Hz, 6 H) 483.1 28-H

(DMSO-d₆) δ ppm 10.49 (s, 1 H), 8.63- 8.71 (m, 1 H), 8.52 (d, J = 5.8Hz, 1 H), 8.41 (d, J = 9.1 Hz, 1 H), 8.21 (d, J = 3.8 Hz, 1 H), 8.10 (s,1 H), 7.95 (d, J = 8.3 Hz, 1 H), 7.60 (t, J = 8.0 Hz, 1 H), 7.50 (d, J =2.3 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 7.39 (d, J = 2.5 Hz, 1 H), 7.19(dd, J = 5.7, 2.7 Hz, 1 H), 7.14 (dd, J = 8.8, 2.5 Hz, 1 H), 6.77 (d, J= 3.5 Hz, 1 H), 3.40-3.46 (m, 4 H), 3.28-3.38 (m, 3 H). 499.1 28-I

(DMSO-d₆) δ ppm 10.50 (s, 1 H), 8.90 (d, J = 8.3 Hz, 1 H), 8.52 (d, J =5.6 Hz, 1 H), 8.40 (d, J = 8.8 Hz, 1 H), 8.21 (d, J = 3.5 Hz, 1 H), 8.11(s, 1 H), 7.96 (d, J = 8.3 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.49 (d,J = 2.3 Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.37 (d, J = 2.5 Hz, 1 H),7.10-7.21 (m, 2 H), 6.78 (d, J = 3.5 Hz, 1H), 4.32-4.45 (m, 1H),2.09-2.21 (m, 4H), 1.59-1.71 (m, 2H). 495.1 28-J

(DMSO-d₆) δ ppm 10.46 (br. S., 1 H), 8.80 (t, J = 6.1 Hz, 1 H), 8.51 (d,J = 5.6 Hz, 1 H), 8.38 (d, J = 9.1 Hz, 1 H), 8.18 (d, J = 3.3 Hz, 1 H),8.10 (s, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.62 (t, J = 8.0 Hz, 1 H),7.51 (d, J = 2.3 Hz, 1 H), 7.46 (d, J = 7.1 Hz, 1 H), 7.38 (d, J = 2.5Hz, 1 H), 3.26-3.37 (m, 6 H), 3.22 (s, 3 H). 513.1 28-K

(ACETONITRILE-d₃)

 ppm 8.84 (s, 1 H) 8.49 (d, J = 6.06 Hz, 1 H) 8.08 (s, 1 H) 7.87 (s, 1H) 7.63-7.68 (m, 2 H) 7.54- 7.58 (m, 1 H) 7.14 (dd, J = 8.97, 7.71 Hz, 1H) 7.01-7.07 (m, 2 H) 6.61 (s, 1 H) 3.70 (s, 3 H) 3.28-3.34 (m, 3 H)2.66 (s, 3 H) 516.9 28-L

(ACETONITRILE-d₃)

 ppm 8.83 (br. S, 1 H) 8.36 (d, J = 5.81 Hz, 1 H) 7.97 (s, 2 H) 7.77 (d,J = 8.34 Hz, 1 H) 7.53 (d, J = 8.08 Hz, 2 H) 7.44 (d, J = 7.58 Hz, 1 H)7.38 (d, J = 2.53 1 H) 6.93-7.07 (m, 2 H) 6.48 (s, 1 H) 2.79 (m, 3 H)2.54 (s, 3 H) 486.9

EXAMPLE 294-Fluoro-5-(2-hydroxymethyl-pyridin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Example 28-K (960 mg, 1.86 mmol) is dissolved in MeOH (30 ml) and cooledto 0° C. with stirring under nitrogen. At this time, NaBH₄ (392 mg, 10.4mmol) is added and the reaction is stirred at 0° C. The reaction isallowed to warm to rt and stirred for 1.5 h. The reaction is stopped andconcentrated under reduced pressure. The resulting foam is taken up intoEtOAc and 0.5N NaOH is added. The biphasic solution is vigorously shakenand the layers allowed to separate. The aqueous layer is washed a secondtime with EtOAc and the combined organics are dried over Na₂SO₄,filtered and concentrated in vacuo. The resulting crude oil is separatedby FCC. MS (ESI) m/z 459.9 (M+1); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm8.39 (d, J=6.06 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J=7.83 Hz, 1H), 7.66 (s,1H), 7.56 (t, J=7.96 Hz, 1H), 7.45-7.53 (m, 2H), 7.04 (dd, J=8.84, 7.33Hz, 1H), 6.84 (dd, J=5.94, 2.40 Hz, 1H), 6.78 (d, J=2.27 Hz, 1H), 6.54(s, 1H), 4.67 (s, 2 H), 2.67 (s, 3H).

EXAMPLE 305-(2-((Dimethylamino)methyl)pyridin-4-yloxy)-4-fluoro-2-methyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

In a 100 mL round-bottomed flask is added Example 29 (865 mg, 1.88 mmol)in DCM (20 mL) to give a suspension. The reaction vessel is cooled to 0°C. using an ice/water bath. MsCl (300 μl, 3.85 mmol) and DIPEA (600 μl,3.44 mmol) are added via syringe. The reaction mixture quickly becomeshomogenous and is warmed to rt with stirring. After 2 h, the reaction isstopped and concentrated in vacuo. The resulting brown oil is absorbedonto a prepacked 12 g silica gel cartridge. The product is eluted usinga 0-100% EtOAc/heptane gradient to give(4-(4-Fluoro-2-methyl-1-(3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyridine-2-yl)methylmethanesulfonate [MS (ESI) m/z 538.9 (M+1)] along with a minor productthat is identified as5-(2-(chloromethyl)pyridine-4-yloxy)-4-fluoro-2-methyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.MS (ESI) m/z 479.9 (M+1).

In a 1-DRAM vial the above mixture (140 mg, 0.260 mmol) is taken up inDCM (1.5 mL) to give a orange solution. Dimethylamine in MeOH (2.0 M,0.4 mL, 0.800 mmol) is added and the reaction is stirred at rt. Afterstanding overnight the reaction mixture is loaded onto a 12-g silica gelprepacked solid load cartridge. The residual solvent is removed via highpressure air blowing through the plug. The desired product is elutedusing a 0-10% MeOH/DCM gradient from the silica gel cartridge to give5-(2-((dimethylamino)methyl)pyridine-4-yloxy)-4-fluoro-2-methyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.MS (ESI) m/z 486.9 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.01 (s, 1H),8.37 (d, J=4.55 Hz, 1H), 8.11 (s, 1H), 7.91 (d, J=7.33 Hz, 1H), 7.67 (t,J=7.96 Hz, 1H), 7.55 (d, J=8.59 Hz, 2H), 7.17 (d, J=7.83 Hz, 1H),6.79-6.94 (m, 2H), 6.66 (s, 1H), 3.46 (s, 2H), 2.59 (s, 3H), 2.13 (s,6H).

EXAMPLE 31 31-A.4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acidtert-butyl ester

7-Benzyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (ref. Org.Proc. Res. Dev. 2005, 9, 80) (36.9 g, 153 mmol) and BOC anhydride (40.1g, 184 mmol) are taken up in MeOH (600 mL). The vessel is purged withargon and palladium on carbon (10% w/w; wet) (5.0 g) is added. Thecontents are then stirred under a hydrogen atmosphere (1 atm) for 18 h.At that time the suspension is filtered over Celite® and the resultingsolution is concentrated to give the title compound. MS (ESI) m/z 252.0(M+1).

31-B. 4-Chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acidtert-butyl ester

Triphenylphosphine (17.3 g, 66.1 mmol) is added to a solution of4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acidtert-butyl ester (8.30 g, 33.0 mmol), CCl₄ (9.6 mL, 99 mmol), and1,2-dichloroethane (250 mL). The solution is heated at 70° C. for 2.5 h.The solution is concentrated in vacuo to about 50 mL. The contents ofthe flask are then filtered over a silica gel plug eluting with 60%EtOAc/heptane. The residue following concentration is then furtherseparated via flash chromatography (10-30% EtOAc/heptane) to give thetitle compound.

MS (ESI) m/z 270.0 & 272.0 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm 8.79 (s,1H), 4.65 (s, 2H), 3.74 (t, J=5.8 Hz, 2H), 2.87 (t, J=5.8 Hz, 2H), 1.49(s, 9H).

31-C.4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

To a solution of4-Chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acidtert-butyl ester (5.46 g, 20.2 mmol), 5-hydroxyindole (3.50 g, 26.3mmol) and CH₃CN (100 mL) is added DBU (4.0 mL, 26.3 mmol). The mixtureis then heated at 50° C. for 4 h. At that time the solvent is removed invacuo and the residue separated via FCC (10-50% EtOAc/heptane) to givethe title compound. MS (ESI) m/z 367.1 (M+1).

The following compounds are prepared with similar method.

31-D.4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

MS (ESI) m/z 399.0 (M+1)

31-E.4-(4-Fluoro-1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

MS (ESI) m/z 385.1 (M+1)

31-F.4-(6-Fluoro-1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

MS (ESI) m/z 385.0 (M+1)

EXAMPLE 324-(2-Methyl-1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

To a stirring solution of4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acidtert-butyl ester, Example 31-A, (300 mg, 1.2 mmol) in I (5 mL) is addedPyBOP (800 mg, 1.55 mmol) and DBU (0.2 mL, 1.43 mmol). After 20 min2-methyl-1H-indol-5-ol (211 mg, 1.43 mmol) is added. The mixture is thenstirred at room temperature for 16 h. At that point the reaction isconcentrated under reduced pressure and the residue is dissolved inEtOAc and washed by water and brine. The organic layer is dried oversodium sulfate, concentrated under reduced pressure. The residue ispurified by FCC (EtOAc/heptane from 0% to 40%) to give the titlecompound. MS (ESI) m/z 381.0 (M+1).

EXAMPLE 33 33-A.4-[1-(2-Fluoro-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

Sodium hydride (0.025 g, 0.614 mmol, 60% in mineral oil) is added to asolution of4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-c]pyrimidine-7-carboxylicacid tert-butyl ester, Example 31-C, (0.150 g, 0.409 mmol) and THF (5mL) at 0° C. After 20 min 2-fluoro-5-(trifluoromethyl)phenyl isocyanate(0.168 g, 0.819 mmol) is added. After an additional 1 h the contents ofthe flask are poured into saturated aqueous NaHCO₃ (25 mL) and extractedwith EtOAc (3×25 mL). The combined organic layers are then dried(Na₂SO₄), filtered and concentrated. The crude residue is then separatedvia FCC (20-50% EtOAc/heptane) to provide the title compound. MS (ESI)m/z 572.1 (M+1).

33-B.5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (2-fluoro-5-trifluoromethyl-phenyl)-amide

TFA (1 mL, 13.0 mmol) is added to a solution of4-[1-(2-fluoro-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (0.125 g, 0.219 mmol) and DCM (2.5 mL). After 1 hthe solution is concentrated in vacuo. The residue is taken up in MeOHand neutralized to pH 7 by the addition of NH₄OH and the solution isseparated via semi-prep HPLC (C18; 10-100% I/H₂O with 0.1% NH₄OH) togive5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (2-fluoro-5-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 472.1(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.40 (s, 1H), 8.25 (d, J=8.8 Hz,1H), 8.07 (d, J=3.8 Hz, 1H), 8.03-8.07 (m, 1H), 7.67-7.75 (m, 1H),7.56-7.64 (m, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.11 (dd, J=9.0, 2.4 Hz, 1H),6.79 (d, J=3.5 Hz, 1H), 3.83 (s, 2H), 3.04 (t, J=5.8 Hz, 2H), 2.73 (t,J=5.6 Hz, 2H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 33-C

(DMSO-d₆) δ ppm 10.43 (s, 1 H), 8.54 (s, 1 H), 8.30 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 3.5 Hz, 1 H), 8.11 (s, 1 H), 7.98 (d, J = 8.3 Hz, 1 H),7.65 (t, J = 8.0 Hz, 1 H), 7.44-7.53 (m, 2 H), 7.14 (dd, J = 9.0, 2.4Hz, 1 H), 6.81 (d, J = 3.8 Hz, 1 H), 4.26 (s, 2 H), 3.45 (t, J = 5.9 Hz,2 H), 3.00 (t, J = 5.8 Hz, 2 H) 454.0 33-D

(DMSO-d₆)

 ppm 10.38 (br. S., 1 H), 8.43 (s, 1 H), 8.26 (d, J = 8.8 Hz, 1 H),8.06-8.16 (m, 2 H), 7.95-8.05 (m, 1 H), 7.57 (t, J = 9.7 Hz, 1 H), 7.46(d, J = 2.3 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1 H), 6.80 (d, J = 3.3Hz, 1 H), 3.93 (s, 2 H), 3.14 (t, J = 5.9 Hz, 2 H), 2.79 (t, J = 5.7 Hz,2 H) 472.0 33-E

(MeOD) δ ppm 8.38 (s, 1 H), 8.13 (d, J = 9.09 Hz, 1 H), 8.06 (s, 1 H),7.89 (d, J = 8.34 Hz, 1 H), 7.94 (d, J = 3.79 Hz, 1 H), 7.58 (t, J =7.96 Hz, 1 H), 7.45 (d, J = 7.83 Hz, 1 H), 7.19 (m, 1 H), 6.82 (d, J =3.79 Hz, 1 H), 3.96 (s, 2 H), 3.19 (t, J = 5.94 Hz, 2 H), 2.91 (t, J =5.68 Hz, 2 H). 471.9 33-F

(MeOD) δ ppm 8.39 (s, 1 H), 8.19 (d, J = 11.62 Hz, 1 H), 8.05 (s, 1 H),7.95 (d, J = 3.54 Hz, 1 H), 7.90 (d, J = 8.34 Hz, 1 H), 7.58 (t, J =7.96 Hz, 1 H), 7.45 (d, J = 7.83 Hz, 1 H), 7.50 (d, J = 7.58 Hz, 1 H),6.75 (d, J = 3.79 Hz, 1 H), 3.96 (s, 2 H), 3.19 (t, J = 5.94 Hz, 2 H),2.91 (t, J = 5.56 Hz, 2 H). 471.9 33-G

(MeOD) δ ppm 8.38 (s, 1 H), 8.18 (d, J = 11.37 Hz, 1 H), 8.04 (dd, J =6.19, 2.65 Hz, 1 H), 7.92 (d, J = 3.79 Hz, 1 H), 7.95 (br. S., 1 H),7.50 (d, J = 7.58 Hz, 1 H), 7.33-7.37 (m, 1 H), 6.75 (d, J = 3.79 Hz, 1H), 3.96 (s, 2 H), 3.19 (t, J = 5.94 Hz, 2 H), 2.91 (t, J = 5.56 Hz, 2H). 489.9 33-H

(DMSO-d₆) δ ppm 10.53 (br. S., 1 H), 8.40 (s, 1 H), 8.26 (d, J = 8.8 Hz,1 H), 8.09 (d, J = 3.8 Hz, 1 H), 7.83-7.94 (m, 2 H), 7.46 (d, J = 2.5Hz, 1 H), 7.39-7.45 (m, 1 H), 7.13 (dd, J = 9.0, 2.4 Hz, 1 H), 6.81 (d,J = 3.8 Hz, 1 H), 3.82 (s, 2 H), 3.04 (t, J = 5.8 Hz, 2 H), 2.73 (t, J =5.7 Hz, 2 H) 472.0 33-I

(DMSO-d₆) δ ppm 10.22 (br. S., 1 H), 8.40 (s, 1 H), 8.24 (d, J = 8.8 Hz,1 H), 8.08 (d, J = 3.5 Hz, 1 H), 7.89-8.00 (m, 1 H), 7.64-7.74 (m, 1 H),7.36-7.53 (m, 2 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1 H), 6.80 (d, J = 3.5Hz, 1 H), 3.83 (s, 2 H), 3.04 (t, J = 5.8 Hz, 2 H), 2.73 (t, J = 5.6 Hz,2 H). 472.0 33-J

(DMSO-d₆) δ ppm 10.43 (br. S., 1 H), 8.40 (s, 1 H), 8.26 (d, J = 9.1 Hz,1 H), 8.22 (d, J = 2.8 Hz, 1 H), 8.09 (d, J = 3.8 Hz, 1 H), 8.00 (d, 1H), 7.75 (d, J = 8.8 Hz, 1 H), 7.44-7.48 (m, 1 H), 7.08- 7.16 (m, 1 H),6.79 (d, J = 3.5 Hz, 1 H), 3.82 (s, 2 H), 3.03 (t, J = 5.8 Hz, 2 H),2.72 (t, J = 5.6 Hz, 2 H) 488.0 33-K

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 8.09 (d, J =3.5 Hz, 2 H), 7.84 (d, J = 8.6 Hz, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.45(d, J = 2.5 Hz, 1 H), 7.10 (dd, J = 9.0, 2.4 Hz, 1 H), 6.78 (d, J = 3.5Hz, 1 H), 3.84 (s, 2 H), 3.05 (t, J = 5.8 Hz, 2 H), 2.74 (t, J = 5.7 Hz,2 H). 488.0 33-L

(MeOD) δ ppm 8.36 (s, 1 H), 8.07 (s, 1 H), 7.86 (s, 1 H), 7.68 (d, J =8.84 Hz, 1 H), 7.59 (s, 1 H), 7.46 (d, J = 8.59 Hz, 1 H), 7.72 (d, J =1.77 Hz, 1 H), 6.99 (dd, J = 9.09, 2.27 Hz, 1 H), 6.44 (s, 1 H), 3.94(s, 2 H), 3.17 (t, J = 5.94 Hz, 2 H), 2.85- 2.89 (m, 2 H), 2.61 (s, 3H). 467.9 33-M

(DMSO-d₆) δ ppm 10.99 (s, 1 H) 8.57 (s, 1 H) 8.12 (s, 1 H), 7.92 (d, J =6.57 Hz, 1 H) 7.64-7.69 (m, 1 H) 7.53 (d, J = 8.84 Hz, 2 H) 7.15 (dd, J= 8.84, 7.83 Hz, 1 H) 6.62 (s, 1 H) 4.33 (s, 2 H) 3.51 (t, J = 6.06 Hz,2 H) 3.05 (s, 2 H) 2.59 (s, 3 H) 1.75 (s, 1 H) 485.8 33-N

(MeOD)

 ppm 8.37 (s, 1 H) 8.07 (dd, J = 6.32, 2.78 Hz, 1 H) 7.90 (br. S., 1 H)7.49 (d, J = 8.84 Hz, 1 H) 7.39 (t, J = 9.60 Hz, 1 H) 7.07 (dd, J =8.72, 7.45 Hz, 1H) 6.52 (s, 1 H) 3.96 (s, 2 H) 3.19 (t, J = 5.94 Hz, 2H) 2.90 (t, J = 5.43 Hz, 2 H) 2.61 (s, 3 H) 503.1

EXAMPLE 345-(7-Acetyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of Example 33-C (0.150 g, 0.331 mmol), Et₃N (0.14 mL,0.792 mmol) and DCM (5 mL) is added acetic anhydride (0.05 mL, 0.496mmol). After 0.5 h the solution is concentrated and then separated viasemi-prep HPLC (10-90% I/H₂O with 0.1% NH₄OH) to give the titlecompound. MS (ESI) m/z 496.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.38 (s, 1H), 8.45-8.53 (m, 1H), 8.27 (d, J=9.1 Hz, 1H), 8.12 (d, J=3.8Hz, 1H), 8.10 (s, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H),7.50 (d, J=7.8 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.14 (dd, J=9.0, 2.4 Hz,1H), 6.80 (d, J=3.5 Hz, 1H), 4.63 (s, 2H), 3.81 (t, J=5.9 Hz, 2H), 2.93(t, J=5.7 Hz, 2H), 2.16 (s, 3H).

EXAMPLE 355-(7-Methanesulfonyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of Example 33-C (0.150 g, 0.331 mmol), Et₃N (0.14 mL,0.792 mmol) and DCM (5 mL) is added methanesulfonyl chloride (0.04 mL,0.496 mmol). After 0.5 h the solution is concentrated and then separatedvia semi-prep HPLC (10-90% I/H₂O with 0.1% NH₁₀H) to give the titlecompound. MS (ESI) m/z 532.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.39 (s, 1H), 8.51 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 8.13 (d, J=3.8 Hz,1H), 8.10 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.51(s, 1H), 7.49 (d, J=2.3 Hz, 1H), 7.15 (dd, J=9.0, 2.4 Hz, 1H), 6.81 (d,J=3.3 Hz, 1H), 4.39 (s, 2H), 3.58 (t, J=5.9 Hz, 2H), 3.06 (s, 3H), 2.97(t, J=5.7 Hz, 2H).

EXAMPLE 364-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid ethyl ester

To a solution of Example 33-C (0.200 g, 0.441 mmol), pyridine (0.11 mL,1.32 mmol) and DCM (5 mL) is added ethyl chloroformate (0.06 mL, 0.661mmol). After 0.5 h the solution is concentrated and then separated viasemi-prep HPLC (10-90% I/H₂O with 0.1% NH₄OH) to give the titlecompound. MS (ESI) m/z 526.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.38 (s, 1H), 8.49 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.12 (d, J=3.8 Hz,1H), 8.10 (s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.50(d, J=7.8 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.14 (dd, J=8.8, 2.3 Hz, 1H),6.80 (d, J=3.5 Hz, 1H), 4.57 (br. S., 2H), 4.12 (q, J=7.1 Hz, 2H), 3.76(t, J=5.4 Hz, 2H), 2.86 (t, J=5.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H).

EXAMPLE 37 37-A.5-(7-Ethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of the TFA salt of Example 33-C (0.720 g, 1.59 mmol),acetaldehyde (0.18 mL, 3.18 mmol), Et₃N (0.44 mL, 3.18 mmol) and DCE (10mL) is added sodium triacetoxyborohydride (0.673 g, 0.3.18 mmol). After1 h the suspension is poured into brine (50 mL) and extracted with DCM(3×50 mL). The combined organic layers are then dried (Na₂SO₄) filteredand concentrated. The reside is the separated via semi-prep HPLC (10-90%I/H₂O with 0.1% NH₄OH) to give the title compound. MS (ESI) m/z 482.2(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.38 (br. S., 1H), 8.42 (s, 1H),8.28 (d, J=9.1 Hz, 1H), 8.11 (d, J=3.8 Hz, 1H), 8.10 (s, 1H), 7.96 (d,J=9.1 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.46 (d,J=2.5 Hz, 1H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 6.78 (d, J=3.8 Hz, 1H),3.57 (s, 2H), 2.74-2.87 (m, 4H), 2.59 (q, J=7.2 Hz, 2H), 1.12 (t, J=7.2Hz, 3H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 37-B

(MeOD) δ ppm 8.39 (s, 1 H), 8.33 (d, J = 9.1 Hz, 1 H), 8.04 (dd, J =6.3, 2.8 Hz, 1 H), 7.89- 7.95 (m, 2 H), 7.40 (d, J = 2.3 Hz, 1 H), 7.36(t, J = 9.6 Hz, 1 H), 7.10 (dd, J = 9.0, 2.4 Hz, 1 H), 6.74 (d, J = 3.0Hz, 1 H), 3.68 (s, 2 H), 2.94- 3.00 (m, 2 H), 2.87-2.92 (m, 2 H), 2.71(q, J = 7.2 Hz, 2 H), 1.24 (t, J = 7.2 Hz, 3 H). 500.1 37-C

(MeOD) δ ppm 8.53 (s, 1 H), 8.36 (d, J = 9.1 Hz, 1 H), 8.07 (s, 1 H),7.96 (d, J = 3.8 Hz, 1 H), 7.90 (d, J = 8.1 Hz, 1 H), 7.58 (t, J = 8.0Hz, 1 H), 7.40-7.48 (m, 2 H), 7.13 (dd, J = 9.0, 2.4 Hz, 1 H), 6.75 (d,J = 3.8 Hz, 1 H), 4.46 (br. S., 2 H), 3.70 (br. S., 2 H), 3.24 (t, J =5.7 Hz, 2 H), 1.85-1.97 (m, 2 H), 1.29 (s, 2 H), 1.10 (t, J = 7.5 Hz, 3H). 496.1 37-D

(MeOD) δ ppm 8.53 (s, 1 H), 8.36 (d, J = 9.1 Hz, 1 H), 8.07 (s, 1 H),7.96 (d, J = 3.8 Hz, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.58 (t, J = 8.0Hz, 1 H), 7.38-7.47 (m, 2 H), 7.12 (dd, J = 9.1, 2.3 Hz, 1 H), 6.75 (d,J = 3.8 Hz, 1 H), 4.45 (br. S., 2 H), 3.77-3.87 (m, 1 H), 3.67 (br. S.,2 H), 3.25 (br. S., 2 H), 1.50 (d, J = 6.6 Hz, 6 H). 496.1 37-E

(MeOD) δ ppm 8.39 (s, 1 H), 8.33 (d, J = 9.1 Hz, 1 H), 8.06 (s, 1 H),7.93 (d, J = 3.5 Hz, 1 H), 7.90 (d, J = 9.9 Hz, 1 H), 7.57 (t, J = 8.0Hz, 1 H), 7.44 (d, J = 7.1 Hz, 1 H), 7.40 (d, J = 2.3 Hz, 1 H), 7.11(dd, J = 9.0, 2.4 Hz, 1 H), 6.74 (d, J = 3.5 Hz, 1 H), 3.64 (s, 2 H),2.98 (t, J = 5.8 Hz, 2 H), 2.83-2.90 (m, 2 H), 2.54 (s, 3 H). 468.0 37-F

(MeOD)

 ppm 8.38 (s, 1 H) 8.07 (s, 1 H) 7.87 (d, J = 8.08 Hz, 1 H) 7.59 (t, J =8.08 Hz, 1 H) 7.48 (m, 2 H) 7.06 (dd, J = 8.72, 7.45 Hz, 1 H) 6.51 (s, 1H) 3.68 (s, 2 H) 2.97 (d, J = 5.81 Hz, 2 H) 2.91 (d, J = 5.31 Hz, 2 H)2.70 (q, J = 7.07 Hz, 2 H) 2.61 (s, 3 H) 1.23 (t, J = 7.33 Hz, 3 H)513.2

EXAMPLE 38 38-A.5-[6-(4-Amino-piperidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid-(3-trifluoromethyl-phenyl)-amide

To a solution of methanesulfonic acid6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethylester, Example 18-B, (0.6 g, 1.19 mmol) in THF (8 mL) and DMF (8 mL) isadded tert-butyl piperidin-4-ylcarbamate (0.713 g, 3.56 mmol) followedby DIEA (0.62 mL, 3.56 mmol) and sodium iodide (0.534 g, 3.56 mmol). Thesolution is stirred at it for 2.5 h. before being partitioned betweenEtOAc and sat aq NaHCO₃. The layers are separated and the organic layeris washed further with brine and then dried over Na₂SO₄, filtered andconcentrated. After concentration the residue is separated by FCC(20-80% EtOAc/heptane). The product is then treated with 50% TFA in DCMat it for 1 h. After concentration, the residue is purified by semi-prepHPLC (20-55% CAN/H₂O with 0.1% NH₄OH) to provide the title compound. MS(ESI) m/z 511.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.66 (s, 1H),8.29 (d, J=9.0 Hz, 1H), 8.16 (d, J=3.7 Hz, 1H), 8.11 (s, 1H), 7.98 (d,J=8.2 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.46-7.54 (m, 2H), 7.16 (dd,J=8.9, 2.3 Hz, 1H), 7.03 (s, 1H), 6.80 (d, J=3.7 Hz, 1H), 3.57 (s, 2H),2.74-2.90 (m, 3H), 2.11 (t, J=10.8 Hz, 2H), 1.78 (d, J=12.4 Hz, 2H),1.31-1.51 (m, 2H).

38-B.5-[6-(4-Acetylamino-piperidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of5-[6-(4-amino-piperidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid-(3-trifluoromethyl-phenyl)-amide (0.159 g, 0.312 mmol) in THF (2mL) and DCM (2 mL) at 0° C. is added DIEA (0.163 mL, 0.935 mmol) andacetyl chloride (29 uL, 0.405 mmol). The reaction is stirred at 0° C.for 2.5 h before being partitioned between EtOAc and sat aq NaHCO₃. Thelayers are separated and the organic layer is washed further with brineand then dried over Na₂SO₄. After concentration the residue is taken upin THF (8 mL) and MeOH (8 mL) and treated with K₂CO₃ at rt for 0.5 h.The mixture is then filtered and concentrated. The residue is thenseparated by semi-prep HPLC (20-50% I/H₂O with 0.1% NH₄OH) to providethe title compound.

MS (ESI) m/z 553.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.66 (d, J=1.0Hz, 1H), 8.49-8.61 (m, 1H), 8.12 (d, J=3.5 Hz, 1H), 8.04 (s, 1H),7.69-7.83 (m, 2H), 7.37-7.51 (m, 2H), 7.14-7.26 (m, 1H), 7.04 (d, J=9.1Hz, 1H), 6.96 (s, 1H), 6.55-6.63 (m, 1H), 3.44-3.59 (m, 3H), 2.72-2.82(m, 2H), 2.06-2.18 (m, 2H), 1.76 (s, 3H), 1.63-1.73 (m, 2H), 1.27-1.42(m, 2H), 1.24 (s, 1H).

The following compounds are prepared with similar method.

38-C.5-{6-[4-(Cyclopropanecarbonyl-amino)-piperidin-1-ylmethyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 579.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.66 (s, 1H),8.29 (d, J=8.8 Hz, 1H), 8.14 (d, J=3.5 Hz, 1H), 8.10 (s, 1H), 7.96 (t,J=8.6 Hz, 2H), 7.65 (t, J=8.0 Hz, 1H), 7.47-7.53 (m, 2H), 7.17 (dd,J=9.0, 2.4 Hz, 1H), 7.04 (s, 1H), 6.81 (d, J=3.5 Hz, 1H), 3.48-3.62 (m,3H), 2.80 (d, J=11.1 Hz, 2H), 2.14 (t, J=10.7 Hz, 2H), 1.72 (d, J=12.4Hz, 2H), 1.47-1.57 (m, 1H), 1.33-1.48 (m, 2H), 0.55-0.68 (m, 4H).

EXAMPLE 395-[6-(4-Methanesulfonylamino-piperidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Prepared in similar manner as described for Example 35. MS (ESI) m/z589.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.66 (d, J=1.0 Hz, 1H),8.33-8.58 (m, 1H), 8.12 (d, J=3.8 Hz, 1H), 8.05 (s, 1H), 7.74-7.93 (m,1H), 7.36-7.60 (m, 2H), 7.01-7.13 (m, 2H), 6.99 (s, 1H), 6.56-6.74 (m,1H), 3.54 (s, 2H), 3.04-3.21 (m, 1H), 2.90 (s, 3H), 2.72-2.84 (m, 2H),2.06-2.20 (m, 2 H), 1.74-1.87 (m, 2H), 1.36-1.54 (m, 2H).

EXAMPLE 405-[7-(3-Diethylamino-propionyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of5-(5,6,7,8-tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide, Example 31-C, (120 mg, 0.26mmol), HATU (198 mg, 0.52 mmol), DIEA (0.2 mL, 1.30 mmol) and DMF (5 mL)is added 3-diethylamino-propionic acid hydrochloride (47 mg, 0.26 mmol).After stirring at rt for 2 h the contents of the flask are partitionedbetween DCM and 10% aqueous LiCl. Organic layer is removed, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue is thenseparated via semi-prep HPLC (C18; 10-100% I/H₂O with 0.1% NH₄OH) togive the title compound. MS (ESI) m/z 581.2 (M+1); ¹H NMR (400 MHz,MeOD) δ ppm 8.40-8.48 (m, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.06 (s, 1H),7.94 (d, J=3.5 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H),7.36-7.47 (m, 2H), 7.10 (dd, J=9.0, 2.1 Hz, 1H), 6.74 (d, J=3.8 Hz, 1H),4.71-4.79 (m, 2H), 3.85-4.05 (m, 2H), 3.20 (d, J=5.8 Hz, 2H), 2.84-3.08(m, 8H), 1.23 (q, J=7.1 Hz, 6H).

EXAMPLE 41 41-A.{4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4d]pyrimidin-7-yl}-aceticacid tert-butyl ester

A solution of5-(5,6,7,8-tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide, Example 33-C, (250 mg, 0.55mmol), bromo tert-butylacetate (204 μL, 1.38 mmol), TEA (384 μL, 2.76mmol) and ACN (5 mL) is stirred at room temperature. Followingcompletion of the reaction the contents of the flask are partitionedbetween DCM and brine. Organic layer is dried over anhydrous Na₂SO₄,concentrated, and the residue is separated via FCC (50-100%EtOAc/heptane) to give the title compound. MS (ESI) m/z 568.1 (M+1).

41-B.{4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-aceticacid

A solution of{4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-aceticacid tert-butyl ester (250 mg, 0.44 mmol), DCM (5 mL), and TFA (5 mL) isstirred at rt for 1 h. The solution is concentrated in vacuo andseparated via semi-prep HPLC (C18; 10-100% I/H₂O with 0.1% NH₄OH) togive the title compound. MS (ESI) m/z 512.0 (M+1); ¹H NMR (400 MHz,MeOD) δ ppm 8.41 (s, 1H), 8.33 (d, J=9.1 Hz, 1H), 8.06 (s, 1H), 7.93 (d,J=3.5 Hz, 1H), 7.89 (s, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.38-7.47 (m, 2H),7.12 (dd, J=9.0, 2.4 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 4.08 (s, 2H), 3.56(s, 2H), 3.26 (t, J=6.1 Hz, 2H), 3.07 (t, J=5.7 Hz, 2H).

41-C.5-(7-Methylcarbamoylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

A combination of{4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-aceticacid (246 mg, 0.48 mmol), HATU (366 mg, 0.56 mmol), DIEA (0.4 mL, 2.41mmol) methylamine (201 μL, 0.48 mmol, 2.0 M THF solution) and DMF (10mL) is stirred in a sealed tube at rt for 2 h. Reaction is partitionedbetween DCM and 10% aqueous LiCl. Organic layer is then dried overanhydrous Na₂SO₄, concentrated, and the residue separated via semi-prepHPLC (C18; 10-100% I/H₂O with 0.1% TFA). The pooled fractions arediluted with saturated aqueous NaHCO₃ and extracted with EtOAc. Dryingof the organic layer over Na₂SO₄, followed by filtration andconcentration provided the title compound. MS (ESI) m/z 525.0 (M+1); ¹HNMR (400 MHz, MeOD) δ ppm 8.38 (s, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.06 (s,1H), 7.94 (d, J=3.5 Hz, 1H), 7.91 (s, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.44(d, J=7.8 Hz, 1H), 7.40 (d, J=2.3 Hz, 1H), 7.10 (dd, J=8.8, 2.3 Hz, 1H),6.74 (d, J=3.5 Hz, 1H), 3.75 (s, 2H), 3.00 (d, J=5.3 Hz, 2H), 2.90-2.96(m, 2H), 2.80 (s, 3H).

EXAMPLE 42 42-A.4-Oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acidtert-butyl ester

6-Benzyl-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one (36.9 g, 153mmol) and BOC anhydride (40.1 g, 184 mmol) are taken up in MeOH (600mL). The vessel is purged with argon and palladium on carbon (10% w/w;wet) (5.0 g) is added. The contents are then stirred under a hydrogenatmosphere (1 atm) for 18 h. At that time the suspension is filteredover Celite® and the solution concentrated to give the title compound.MS (ESI) m/z 252.0 (M+1).

42-B. 4-Chloro-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acidtert-butyl ester

Triphenylphosphine (12.8 g, 48.7 mmol) is added to a solution of Example42-A (6.08 g, 24.1 mmol), CCl₄ (7.0 mL, 72.3 mmol), and1,2-dichloroethane (250 mL). The solution is then warmed to 70° C. After2.5 h the solution is concentrated in vacuo to about 50 mL. The residueis then separated via FCC (10-30% EtOAc/heptane) to give the titlecompound. MS (ESI) m/z 270.0 & 271.9 (M+1).

42-C.4-(1H-Indol-5-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester

To a solution of Example 42-B (0.250 g, 0.926 mmol), 5-hydroxyindole(0.160 g, 1.20 mmol) and CH₃CN (5 mL) is added DBU (0.18 mL, 1.20 mmol).The mixture is then warmed to 50° C. for 3 h. At that time the solventis removed in vacuo and the residue separated via FCC (10-50%EtOAc/heptane) to give the title compound. MS (ESI) m/z 367.1 (M+1).

42-D.4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester

Sodium hydride (0.030 g, 0.749 mmol, 60% in mineral oil) is added to asolution of Example 42-C (0.183 g, 0.499 mmol) and THF (5 mL) at 0° C.After 15 min 3-(trifluoromethyl)-phenyl isocyanate (0.14 mL, 0.0.998mmol) is added. After an additional 1.5 h the contents of the flask arepoured into pH 7 buffer (50 mL) and extracted with DCM (2×25 mL). Thecombined organic layers are then dried (Na₂SO₄), filtered andconcentrated. The crude residue is then separated via FCC (20-50%EtOAc/heptane). MS (ESI) m/z 554.0 (M+1).

42-E.5-(5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

TFA (1 mL) is added to a solution of Example 42-D (0.136 g, 0.245 mmol)and DCM (5 mL). After 1 h the solution is concentrated in vacuo. Theresidue is taken up in MeOH and neutralized to pH 7 by the addition ofNH₄OH and then separated via semi-prep HPLC (10-90% I/H₂O with 0.1%NH₄OH) to give the title compound. MS (ESI) m/z 454.0 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.38 (s, 1H), 8.46 (s, 1H), 8.27 (d, J=9.1 Hz, 1H),8.12 (d, J=3.8 Hz, 1H), 8.10 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.65 (t,J=8.0 Hz, 1H), 7.50 (d, J=7.3 Hz, 1H), 7.46 (s, 1H), 7.12 (dd, J=9.0,2.4 Hz, 1H), 6.80 (d, J=3.5 Hz, 1H), 3.92-4.09 (m, 2H), 3.17 (t, J=5.7Hz, 2H), 2.81 (t, J=5.7 Hz, 2H).

EXAMPLE 43 43-A.5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

5-(5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (Example 42-E, 125 mg, 0.28 mmol),paraformaldehyde (16.6 mg, 0.55 mmol), NaBH(Oac)₃ (117 mg, 0.55 mmol)and acetic acid (32 uL, 0.55 mmol) are dissolved in 1,2-DCE (7.5 mL) andheated at 60° C. for 4 h. The reaction mixture is then partitionedbetween DCM and saturated aqueous NaHCO₃. The organic layer is thendried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude residueis separated via FCC (MeOH/EtOAc 1:9 to MeOH/EtOAc 2:8) to give thetitle compound. MS (ESI) m/z 468.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm8.41 (s, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.93 (d, J=3.5 Hz,1H), 7.90 (d, J=9.3 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.6 Hz,1H), 7.41 (d, J=2.3 Hz, 1H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.74 (d,J=3.8 Hz, 1H), 3.74 (s, 2H), 2.96-3.04 (m, 2H), 2.87-2.94 (m, 2H), 2.57(s, 3H).

The following compounds are prepared with similar method.

43-B.5-(6-Ethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

A mixture of5-(5,6,7,8-tetrahydro-pyrido[4,3-a]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (Example 42-E, 125 mg, 0.28 mmol),acetaldehyde (31 μL, 0.55 mmol), NaBH(Oac)₃ (117 mg, 0.55 mmol) and TEA(77 uL, 0.55 mmol) in 1,2-DCE at rt for 4 h. The mixture is thenpartitioned between DCM and saturated aqueous NaHCO₃. The organic layeris dried over anhydrous Na₂SO₄ and concentrated in vacuo. The cruderesidue is then separated via FCC (MeOH/EtOAc 1:9 to MeOH/EtOAc 2:8) togive the title compound (74 mg, 55%). MS (ESI) m/z 482.1 (M+1); ¹H NMR(400 MHz, MeOD) δ ppm 8.57 (s, 1H), 8.36 (d, J=9.1 Hz, 1H), 8.07 (s,1H), 7.97 (d, J=3.8 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.58 (t, J=8.1 Hz,1H), 7.42-7.48 (m, 2H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 6.76 (d, J=3.8 Hz,1H), 3.43-3.54 (m, 3H), 3.26 (br. S., 3H), 1.51 (t, J=7.3 Hz, 3H).

EXAMPLE 44 44-A.4-Oxo-3,4,5,7-tetrahydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acidtert-butyl ester

To a solution of 4-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert-butylester 3-ethyl ester (2 g, 7.8 mmol) in EtOH (78 mL), fomamidinehydrochloride (1.87 g, 25.5 mmol) is added, followed by NaOEt (8.7 mL,27.2 mmol). The reaction is heated at 90° C. for 2 h. The reactionmixture is then evaporated and a saturated solution of ammonium chloride(20 mL) is added followed by DCM (80 mL). The layers are separated andthe aqueous layer is extracted further with DCM (50 mL×3). The organicsare combined, dried and evaporated to give the crude product. The titlecompound is purified using silica gel FCC (gradient elution 100% DCM to94% DCM/6% MeOH). MS (ESI) m/z 238.2 (M+1).

44-B.4-(1H-Indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

To a solution of4-oxo-3,4,5,7-tetrahydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acidtert-butyl ester (74 mg, 0.31 mmol) in acetonitrile (3 mL), BOP (179 mg,0.405 mmol) is added followed by DBU (0.094 mL, 0.624 mmol). After 20min 5-hydroxyindole (83 mg, 0.624 mmol) is added. The reaction is leftstirring at rt for 3 h. The reaction mixture is evaporated and the crudeproduct is purified using silica gel FCC (gradient elution 100% heptaneto 60% heptane/40% ethyl acetate) to give the title compound. MS (ESI)m/z 353.1 (M+1).

The following compounds are prepared with similar method.

44-C.4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

MS (ESI) m/z 385.9 (M+1).

44-D.4-(4-Fluoro-1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

Method carried out as above (Example 44-B) using PyBOP in place of BOP.MS (ESI) m/z 369.1 (M−1).

44-E.4-(2-Methyl-1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

Method carried out as above (Example 44-B) using PyBOP in place of BOP.MS (ESI) m/z 365.1 (M−1).

EXAMPLE 45 45-A.4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

To a solution of4-(1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester (3.59 g, 10.2 mmol) in THF (100 mL) at 0° C., NaH(0.611 g, 15.3 mmol) is added. After 10 min,1-isocyanato-3-trifluoromethyl-benzene (2.93 mL, 20.4 mmol) is added andthe reaction is allowed to reach room temperature. After 2.5 h, asaturated solution of NH₄Cl in water (50 mL) is added. The mixture isextracted with EtOAc (×3), and the combined organic extracts are driedand evaporated to give the crude4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester. MS (ESI)m/z 540.9 (M+1).

45-B.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl phenyl)-amide

To a solution of4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20mL), TFA (20 mL, 260 mmol) is added at 0° C. The reaction is allowed toreach room temperature and stirred for an additional 1 h. TFA/DCM areevaporated and then the product is taken up in EtOAc (100 mL) and washedwith dilute NH₄OH in H₂O (20 mL). The organic layer is separated and thewater layer is extracted further with EtOAc (2×). The combined organicsare dried and evaporated. The crude residue is separated via FCC (elutedwith DCM/MeOH/NH₄OH (100:0:0 to 93:6:1)) to give5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl phenyl)-amide. MS (ESI) m/z 440.9 (M+1); ¹H NMR(400 MHz, MeOD) δ ppm 8.55 (s, 1H) 8.33 (d, J=8.84 Hz, 1H) 8.06 (br. S.,1H) 7.89 (d, J=8.34 Hz, 1H) 7.94 (d, J=3.54 Hz, 1H) 7.57 (t, J=7.96 Hz,1H) 7.41-7.46 (m, 2H) 7.13 (dd, J=9.09, 2.27 Hz, 1H) 6.74 (d, J=3.03 Hz,1H) 4.26 (d, J=12.13 Hz, 4H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 45-C

(MeOD) δ ppm 8.55 (s, 1 H) 8.08 (dd, J = 6.32, 2.78 Hz, 1 H) 7.91 (dt, J= 9.03, 3.44 Hz, 1 H) 7.49 (d, J = 8.84 Hz, 1 H) 7.37 (t, J = 9.60 Hz, 1H) 7.08 (dd, J = 8.84, 7.33 Hz, 1 H), 6.50 (s, 1 H) 4.48 (br. S., 2 H)4.37 (br. S., 2 H) 2.60 (d, J = 1.01 Hz, 3 H). 490.9 45-D

(MeOD) δ ppm 8.52 (s, 1 H) 8.32 (d, J = 9.09 Hz, 1 H) 8.04 (dd, J =6.19, 2.15 Hz, 1 H) 7.91 (d, J = 3.54 Hz, 2 H) 7.42 (d, J = 2.02 Hz, 1H) 7.34 (t, J = 9.60 Hz, 1 H) 7.11 (dd, J = 8.97, 2.15 Hz, 1 H) 6.72 (d,J = 3.54 Hz, 1 H) 4.18 (d, J = 8.84 Hz, 4 H). 458.9 45-E

(MeOD) δ ppm 8.57 (s, 1 H) 8.09 (s, 1 H) 7.87 (d, J = 8.08 Hz, 1 H) 7.59(t, J = 7.96 Hz, 1 H) 7.45-7.51 (m, 2 H) 7.10 (dd, J = 8.72, 7.45 Hz, 1H) 6.52 (s, 1 H) 4.53 (br. S., 2 H) 4.41 (br. S., 2 H) 2.61 (s, 3 H).472.0 45-F

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.27 (d, J = 8.84 Hz, 1 H) 8.10 (d, J =3.54 Hz, 1 H) 7.88-7.93 (m, 2 H) 7.49 (d, J = 2.02 Hz, 1 H) 7.41-7.45(m, 1 H) 7.14-7.18 (m, 1 H) 6.81 (br. S., 1 H) 4.08 (s, 4 H). 458.9 45-G

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.24 (d, J = 9.09 Hz, 1 H) 8.09 (d, J =3.54 Hz, 1 H) 7.89-8.01 (m, 1 H) 7.66-7.73 (m, 1 H) 7.45-7.58 (m, 2 H)7.15 (dd, J = 8.97, 2.40 Hz, 1 H) 6.81 (d, J = 3.03 Hz, 1 H) 4.11 (d, J= 13.89 Hz, 4 H). 458.9 45-H

(MeOD) δ ppm 8.53 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 8.15-8.20 (m, 1 H)7.88- 7.92 (m, 1 H) 7.58 (ddd, J = 6.13, 3.98, 2.27 Hz, 1 H) 7.39-7.46(m, 2 H) 7.12 (dd, J = 9.09, 2.02 Hz, 1 H) 6.74 (d, J = 3.79 Hz, 1 H)4.19 (d, J = 9.35 Hz, 4 H). 458.9 45-I

(MeOD) δ ppm 8.53 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 8.15-8.20 (m, 1 H)7.88-7.92 (m, 1 H) 7.58 (ddd, J = 6.13, 3.98, 2.27 Hz, 1 H) 7.39-7.46(m, 2 H) 7.12 (dd, J = 9.09, 2.02 Hz, 1 H) 6.74 (d, J = 3.79 Hz, 1 H)4.19 (d, J = 9.35 Hz, 4 H). 475.9 45-J

(MeOD) δ ppm 8.53 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 8.15-8.20 (m, 1 H)7.88-7.92 (m, 1 H) 7.58 (ddd, J = 6.13, 3.98, 2.27 Hz, 1 H) 7.39-7.46(m, 2 H) 7.12 (dd, J = 9.09, 2.02 Hz, 1 H) 6.74 (d, J = 3.79 Hz, 1 H)4.19 (d, J = 9.35 Hz, 4 H). 475.9 45-K

(MeOD) δ ppm 8.52 (s, 1 H), 8.07 (s, 1 H), 7.87 (d, J = 7.83 Hz, 1 H),7.69 (d, J = 8.59 Hz, 1 H), 7.59 (t, J = 7.71 Hz, 1 H), 7.46 (d, J =8.08 Hz, 1 H), 7.30 (d, J = 2.02 Hz, 1 H), 7.02 (dd, J = 8.84, 2.27 Hz,1 H), 6.44 (s, 1 H) 4.18 (br. S., 4 H), 2.61 (s, 3 H). 453.9 45-L

(MeOD) δ ppm 8.56 (s, 1 H) 8.33 (d, J = 8.84 Hz, 1 H) 7.93 (d, J = 3.54Hz, 1 H) 7.78 (s, 1 H) 7.43-7.59 (m, 6 H) 7.12 (dd, J = 8.84, 2.27 Hz, 1H) 6.75 (d, J = 3.54 Hz, 1 H) 4.30 (d, J = 12.38 Hz, 4 H) 2.31 (s, 3 H).453.0 45-M

(DMSO-d₆) δ ppm 9.67 (s, 1 H) 8.56 (s, 1 H) 8.24 (d, J = 8.84 Hz, 1 H)8.09 (d, J = 3.79 Hz, 1 H) 7.47 (d, J = 2.53 Hz, 1 H) 7.17 (d, J = 7.58Hz, 1 H) 7.12 (dd, J = 5.81, 3.03 Hz, 1 H) 7.10 (s, 1 H) 6.84 (t, J =7.71 Hz, 1 H) 6.75 (d, J = 3.79 Hz, 1 H) 4.09 (d, J = 9.35 Hz, 2 H)4.06-4.12 (m, 2 H) 3.08 (s, 2 H) 1.44 (s, 6 H) 442.1 45-N

(MeOD) δ ppm 8.53 (s, 1 H) 8.14 (d, J = 9.09 Hz, 1 H) 8.06 (s, 1 H) 7.95(d, J = 3.79 Hz, 1 H) 7.90 (d, J = 7.58 Hz, 1 H) 7.58 (t, J = 8.08 Hz, 1H) 7.45 (d, J = 7.58 Hz, 1 H) 7.21 (dd, J = 8.84, 7.58 Hz, 1 H) 6.83 (d,J = 3.79 Hz, 1 H) 4.33 (s, 2 H) 4.21 (t, J = 1.64 Hz, 2 H) 458.1 45-O

(DMSO-d₆) δ ppm 8.57 (s, 1 H) 8.13 (d, J = 3.79 Hz, 1 H) 8.08 (d, J =8.84 Hz, 1 H) 7.95 (t, J = 7.58 Hz, 1 H) 7.71 (t, J = 7.33 Hz, 1 H) 7.49(t, J = 8.08 Hz, 1 H) 7.31 (d, J = 7.83 Hz, 1 H) 6.93 (d, J = 3.54 Hz, 1H) 4.23 (s, 2 H) 4.10-4.13 (m, 2 H) 476.1

EXAMPLE 46 46-A.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-methoxy-5 trifluoromethyl-phenyl)-amide

To a solution of4-(1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester (158 mg, 0.44 mmol) in DMF (4 mL), CDI (145 mg,0.89 mmol) is added in one portion, followed by TEA (0.37 mL, 2.7 mmol).After 3 h at rt, 3-methoxy-5-trifluoromethyl-phenylamine (514 mg, 2.7mmol) and DMAP (5.5 mg, 0.04 mmol) are added and the reaction is leftstirring for 40 h. Ethyl acetate (2 mL) is added followed by theaddition of 1 N HCl solution (3 mL). The organics are extracted withEtOAc (×3) and concentrated. The crude mixture is dissolved in CH₂Cl₂(10 mL) and cooled to 0° C. and TFA (10 mL, 130 mmol) is added. Thereaction is allowed to reach it over 2 h. The reaction mixture isevaporated, redissolved in EtOAc and few drops of NH₄OH are added tofreebase the amine. The solvent is removed and the residue separated byFCC (DCM/MeOH/NH₄OH (100:0:0 to 93:6:1)) to give5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-methoxy-5 trifluoromethyl-phenyl)-amide. MS (ESI) m/z 471.0(M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.50-8.56 (m, 1H) 7.93 (d, J=3.54Hz, 1H) 7.59 (d, J=19.71 Hz, 2H) 7.42 (d, J=2.27 Hz, 1H) 7.12 (dd,J=8.97, 2.40 Hz, 1H) 6.96 (s, 1H) 6.73 (d, J=3.79 Hz, 1H) 6.52 (s, 1H)4.19 (d, J=8.34 Hz, 4H) 3.76 (s, 3H)

The following compounds are prepared with similar method.

46-B.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide

MS (ESI) m/z 431.9 (M+1) ¹H NMR (400 MHz, MeOD) δ ppm 8.44 (s, 1H) 8.32(d, J=9.09 Hz, 1H) 7.78 (d, J=3.54 Hz, 1H) 7.33 (s, 1H) 7.05 (d, J=7.33Hz, 1H) 6.66 (d, J=3.54 Hz, 1H) 6.43 (br. S., 1H) 5.35 (s, 1H) 4.12 (d,J=13.14 Hz, 4H).

46-C.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-2H-pyrazol-3-yl)-amide

MS (ESI) m/z 418.1 (M+1) ¹H NMR. (400 MHz, MeOD) δ ppm 8.51 (s, 1H) 8.31(d, J=9.09 Hz, 1H) 7.87 (d, J=3.54 Hz, 1H) 7.40 (d, J=2.53 Hz, 1H) 7.10(dd, J=8.97, 2.40 Hz, 1H) 6.69 (d, J=3.54 Hz, 1H) 6.38 (s, 1H) 4.17 (d,J=7.07 Hz, 4H) 1.36 (s, 9H).

EXAMPLE 47 47-A. (±)-2-Benzylamino-propionic acid ethyl ester

Ethyl alanine hydrochloride (5.5 g, 36.8 mmol), benzaldehyde (7.9 mL,77.8 mmol), TEA (10.8 mL, 77.8 mmol) and NaBH(Oac)₃ (16.5 g, 77.8 mmol)are taken up in 1,2-DCE (200 mL) and stirred at rt for 4 h. The reactionis then partitioned between DCM and saturated aqueous NaHCO₃. Theorganic layer is removed, dried over anhydrous Na₂SO₄, and concentratedin vacuo. The crude residue is used without further purification. MS(ESI) m/z 208.2 (M+1).

47-B. (±)-4-[Benzyl-(1-ethoxycarbonyl-ethyl)-amino]-butyric acid methylester

2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyloxo-butanoate (1.7 g, 13.5 mmol), LEA (1.9 mL, 13.5 mmol) and NaBH(Oac)₃(2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for4 h. The reaction is partitioned between DCM and saturated aqueousNaHCO₃. The organic layer is removed, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude residue is used without furtherpurification. MS (ESI) m/z 308.3 (M+1).

47-C. (±)-1-Benzyl-2-methyl-3-oxo-piperidine-4-carboxylic acid methylester

A mixture of 4-[benzyl-(1-ethoxycarbonyl-ethyl)-amino]-butyric acidmethyl ester (1.5 g, 4.9 mmol), potassium tert-butoxide (906 mg, 8.9mmol) and toluene (100 mL) is stirred at rt for 3 h. The mixture is thenpartitioned between DCM and saturated aqueous NH₄Cl. The organic layeris removed, dried over anhydrous Na₂SO₄, and concentrated. The cruderesidue is used without further purification. MS (ESI) m/z 262.2 (M+1).

47-D.(±)-7-Benzyl-8-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one

A mixture of 1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylic acid methylester (1.0 g, 3.9 mmol), formamidine hydrochloride (930 mg, 11.6 mmol),and EtOH (6 mL) is treated with NaOEt solution (5.5 mL, 13.57 mmol, 21%w/w in EtOH) and the reaction is stirred at 90° C. for 2 h. Reaction isconcentrated in vacuo after adjusting to pH 6. Residue is via semi-prepHPLC (C18; 10-100% I/H₂O with 0.1% NH₄OH) to give the title compound. MS(ESI) m/z 256.0 (M+1).

47-E.(±)-8-Methyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

7-Benzyl-8-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-a]pyrimidin-4-one(359 mg, 1.41 mmol) and BOC-anhydride (368 mg, 1.69 mmol) are taken upin MeOH (20 mL) and THF (20 mL). To this solution is added 10% Pd/C (75mg, 20% w/w) and the mixture is stirred under a hydrogen atmosphere (1atm) for 3 h. The mixture is filtered through a Celite® pad and thefilterate is concentrated to give the title compound which is usedwithout further purification. MS (ESI) m/z 266.1 (M+H).

47-F.(±)-4-Chloro-8-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A combination of8-methyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (374 mg, 1.41 mmol), triphenylphosphine (739 mg,2.82 mmol) and carbon tetrachloride (409 uL, 4.23 mmol) and 1,2-DCE (10mL) are heated at 70° C. for 6 h. The solution is then concentrated invacuo and the residue separated via FCC (5-60% EtOAc/heptane). MS (ESI)m/z 284.2 (M+H).

47-G.(±)-4-(1H-Indol-5-yloxy)-8-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

To a solution of4-chloro-8-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (228 mg, 0.80 mmol), 5-hydroxyindole (139 mg, 1.05mmol) and MeCN (5 mL) is added DBU (0.15 mL, 1.05 mmol). The resultingmixture is heated at 80° C. for 4 h. The reaction is then concentratedin vacuo and the residue separated via FCC (5-60% EtOAc/heptane). MS(ESI) m/z 381.1 (M+H).

47-H.(±)-8-Methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A solution of4-(1H-indol-5-yloxy)-8-methyl-5,8-dihydro-6H-pyrido[3,4-a]pyrimidine-7-carboxylicacid tert-butyl ester (224 mg, 0.50 mmol) and THF (8 mL) is cooled to 0°C. To this is added NaH (35 mg, 0.88 mmol, 60% in mineral oil) followedby 3-trifluoromethylisocyanate (164 uL, 1.18 mmol) and the mixture isallowed to warm to room temperature. After completion of the reaction asseen by LCMS the mixture is partitioned between DCM and pH 7 buffersolution. The organic layer is separated, dried over anhydrous Na₂SO₄,and concentrated. The crude residue is purified via FCC (5-60%EtOAc/heptane) to give the title compound. MS (ESI) m/z 568.1 (M+1).

47-I.(±)-5-(8-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

A solution of8-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-a]pyrimidine-7-carboxylicacid tert-butyl ester (217 mg, 0.38 mmol), DCM (5 mL), and TFA (5 mL) isstirred at rt for 2 h. At that point the solution is concentrated invacuo and the residue is separated via semi-prep HPLC (C18; 10-100%I/H₂O with 0.1% NH₄OH) to give the title compound. MS (ESI) m/z 468.1(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.39 (s, 1H), 8.51 (s, 1H), 8.28(d, J=9.1 Hz, 1H), 8.06-8.15 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.65 (t,J=8.0 Hz, 1H), 7.43-7.53 (m, 2H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 6.80 (d,J=3.5 Hz, 1H), 4.19 (q, J=6.6 Hz, 1H), 3.34-3.42 (m, 1H), 3.08-3.20 (m,1H), 2.88 (t, J=5.7 Hz, 2H), 1.49 (d, J=7.1 Hz, 3H).

EXAMPLE 48 48-A.4-[1-(3-Trifluoromethoxy-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A solution of4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (Example 31-C, 300 mg, 0.82 mmol), CDI (265 mg,1.64 mmol), TEA (342 uL, 2.46 mmol), and DCM (5 mL) is stirred at rt for1 h before 3-trifluoromethoxy aniline (435 mg, 2.46 mmol) is added.After an additional 24 h, the reaction is concentrated in vacuo andpurified via FCC (5-90% EtOAc/heptane) to give the title compound. MS(ESI) m/z 564.1 (M+1).

48-B.5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethoxy-phenyl)-amide

A solution of4-[1-(3-trifluoromethoxy-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (212 mg, 0.37 mmol), DCM (5 mL), and TFA (5 mL) isstirred at rt for 2 h. The solution is then concentrated in vacuo andpurified via semi-prep HPLC (C18; 10-100% I/H₂O with 0.1% NH₄OH) to givethe title compound. MS (ESI) m/z 470.0 (M+1); ¹H NMR (400 MHz, MeOD) δppm 8.41 (s, 1H), 8.33 (d, J=9.1 Hz, 1H), 7.93 (d, J=3.8 Hz, 1H), 7.74(s, 1H), 7.62 (dd, J=8.2, 1.1 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 7.40 (d,J=2.3 Hz, 1H), 7.00-7.15 (m, 2H), 6.73 (d, J=3.8 Hz, 1H), 4.05 (s, 2H),3.31-3.29 (obs. M, 2H), 2.96 (t, J=5.7 Hz, 2H).

EXAMPLE 49 49-A.4-(1-{5-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-2H-pyrazol-3-ylcarbamoyl}-1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A solution of4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (Example 31-C, 200 mg, 0.55 mmol), CDI (177 mg,1.10 mmol), TEA (0.23 mL, 1.64 mmol), and DMF (5 mL) is stirred at rtfor 1 h before5-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-2H-pyrazol-3-ylamine(441 mg, 1.64 mmol) and 4-pyrrolidinopyridine (4 mg, 27 umol) are added.After 24 h, the solution is concentrated in vacuo and the residue isseparated via FCC (5-90% EtOAc/heptane) to give the title compound. MS(ESI) m/z 662.3 (M+1).

49-B.5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(2-hydroxy-1,1-dimethyl-ethyl)-2H-pyrazol-3-yl]-amide

A solution of4-O-{5-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-2H-pyrazol-3-ylcarbamoyl}-1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (252 mg, 0.38 mmol), DCM (2 mL), and TFA (2 mL) isstirred at rt for 2 h. At that point the solution is concentrated invacuo and the residue separated via semi-prep HPLC (C18; 10-100% I/H₂Owith 0.1% NH₄OH) to give the title compound. MS (ESI) m/z 448.1 (M+1);¹H NMR (400 MHz, MeOD) δ ppm 1.33 (s, 6H) 2.92 (t, J=5.43 Hz, 2H) 3.25(t, J=5.94 Hz, 2H) 3.30 (s, 2 H) 3.57 (s, 2H) 4.02 (s, 2H) 6.40 (s, 1H)6.70 (d, J=3.54 Hz, 1H) 7.07 (dd, J=8.97, 2.15 Hz, 1H) 7.38 (s, 1H) 7.88(d, J=3.79 Hz, 1H) 8.31 (d, J=9.09 Hz, 1H) 8.39 (s, 1H).

EXAMPLE 50 50-A. 4-(1-Phenyl-ethylamino)-pentanoic acid ethyl ester

Racemic 1-phenylethylamine (10 g, 83 mmol), ethyl levulinate (11.76 mL,83 mmol), NaBH(Oac)₃ (35 g, 165 mmol) and 1,2-DCE (200 mL) are stirredat rt for 4 h. The mixture is then partitioned between DCM and saturatedaqueous NaHCO₃. The organic layer is removed, dried over anhydrousNa₂SO₄, and concentrated in vacuo. The crude residue is used withoutfurther purification. MS (ESI) m/z 250.2 (M+1).

50-B. 4-[Ethoxycarbonylmethyl-(1-phenyl-ethyl)-amino]-pentanoic acidethyl ester

A combination of 4-(1-phenyl-ethylamino)-pentanoic acid ethyl ester(20.5 g, 82 mmol), ethyl glyoxylate (33 mL, 165 mmol, 50% toluenesolution), NaBH(Oac)₃ (34.9 g, 165 mmol), and 1,2-DCE (200 mL) arestirred at rt for 4 h. The mixture is then partitioned between DCM andsaturated aqueous NaHCO₃. The organic layer is removed, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The crude residue is usedwithout further purification. MS (ESI) m/z 336.4 (M+1).

50-C. 2-Methyl-5-oxo-1-(1-phenyl-ethyl)-piperidine-4-carboxylic acidethyl ester

A mixture of 4-[ethoxycarbonylmethyl-(1-phenyl-ethyl)-amino]-pentanoicacid ethyl ester (13 g, 39 mmol), KtOBu (10.9 g, 97 mmol), and toluene(300 mL) is stirred at rt for 3 h. The mixture is then partitionedbetween DCM and saturated aqueous NH₄Cl. The organic layer is removed,dried over anhydrous Na₂SO₄, and concentrated in vacuo. The cruderesidue is separated via FCC (5-30% EtOAc/heptane) to give the titlecompound. MS (ESI) m/z 290.3 (M+1).

50-D.6-Methyl-7-(1-phenyl-ethyl)-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one

A combination of2-methyl-5-oxo-1-(1-phenyl-ethyl)-piperidine-4-carboxylic acid ethylester, (7.4 g, 25.6 mmol), formamidine acetate (7.98 g, 77 mmol), andEtOH (60 mL) is treated with NaOEt solution (36.7 mL, 90 mmol, 21% w/wEtOH solution) and then heated at 90° C. for 4 h. At that point the pHis adjusted to 6 and the mixture is concentrated in vacuo. The residueis partitioned between DCM and saturated aqueous NH₄Cl. The organiclayer is removed, dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude residue is separated via FCC (1-10% MeOH/DCM) to givethe title compound. MS (ESI) m/z 270.1 (M+1).

50-E.(±)-6-Methyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

To a mixture of6-methyl-7-(1-phenyl-ethyl)-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one,(6.8 g, 25.2 mmol), ammonium formate (7.96 g, 126 mmol), BOC-anhydride(8.27 g, 37.9 mmol), MeOH (250 mL), and THF (167 mL) is added 10% Pd/C(1.36 g, 20% w/w) and the reaction is heated at reflux for 3 h. Themixture is then filtered through a Celite® pad and the filterate isconcentrated. The residue is purified via FCC (1-10% MeOH/DCM) to givethe title compound. MS (ESI) m/z 266.1 (M+H).

50-F.(±)-4-Chloro-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A solution of(±)-6-methyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester, (7.5 g, 28.3 mmol), triphenylphosphine (14.8 g,56.5 mmol) and carbon tetrachloride (8.2 mL, 85 mmol) in 1,2-DCE (100mL) is heated at 80° C. for 6 h. At that time the solution isconcentrated in vacuo and the residue is separated via FCC (5-60%EtOAc/heptane) to give the title compound. MS (ESI) m/z 284.1 (M+H).

50-G.(±)-4-(1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A solution of(±)-4-chloro-6-methyl-5,8-dihydro-6H-pyrido[3,4-a]pyrimidine-7-carboxylicacid tert-butyl ester (220 mg, 0.77 mmol), 5-hydroxy indole (155 mg,1.16 mmol) and MeCN (10 mL) is treated with DBU (0.2 mL, 1.16 mmol) andheated at 80° C. for 4 h. The volume is reduced in vacuo and the residueis separated via FCC (5-90% EtOAc/heptane) to give the title compound.MS (ESI) m/z 381.3 (M+H).

The following compounds are prepared with similar method.

50-H.(±)-4-(4-Fluoro-1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

MS (ESI) m/z 399.1 (M+H).

EXAMPLE 51 51-A.(±)-4-[1-(5-tert-Butyl-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A solution of4-(1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (210 mg, 0.55 mmol), CDI (179 mg, 1.10 mmol), TEA(230 uL, 1.65 mmol), and DMF (5 mL) is stirred at rt 1 h before5-tert-butyl-2H-pyrazol-3-ylamine (77 mg, 0.55 mmol) and4-pyrrolidinopyridine (16.4 mg, 0.11 mmol) are added. After 24 h, thereaction is concentrated in vacuo and the purified via FCC (5-90%EtOAc/heptane) to give the title compound. MS (ESI) m/z 546.3 (M+1).

51-B.(±)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-2H-pyrazol-3-yl)-amide

A solution of4-[1-(5-tert-butyl-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (300 mg, 0.55 mmol), DCM (5 mL), and TFA (5 mL) isstirred at it for 2 h. At that point the solution is concentrated andthe residue separated via semi-prep HPLC (C18; 10-100% I/H₂O with 0.1%NH₄OH) to give the title compound. MS (ESI) m/z 446.2 (M+1); ¹H NMR (400MHz, MeOD) δ ppm 8.37 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.88 (d, J=3.5Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.08 (dd, J=9.1, 2.3 Hz, 1H), 6.71 (d,J=3.8 Hz, 1H), 6.38 (br. S., 1H), 6.06 (br. S., 1H), 4.00 (d, J=6.1 Hz,2H), 3.05-3.15 (m, 1H), 3.00 (dd, J=17.2, 3.5 Hz, 1H), 2.47 (dd, J=17.2,10.4 Hz, 1H), 1.36 (s, 9H), 1.34 (d, J=6.3 Hz, 3H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 51-C

(MeOD) δ ppm 8.37 (s, 1 H), 8.32 (d, J = 8.8 Hz, 1 H) 7.88 (d, J = 3.5Hz, 1 H), 7.38 (d, J = 2.3 Hz, 1 H) 7.08 (dd, J = 9.1, 2.3 Hz, 1 H),6.71 (d, J = 3.8 Hz, 1 H), 6.37 (s, 1 H), 3.96 (s, 2 H), 3.19 (t, J =5.9 Hz, 2 H), 2.89 (t, J = 5.7 Hz, 2 H), 1.36 (s, 9 H). 432.1 51-D

(MeOD) δ 8.32-8.40 (m, 2 H), 7.92 (d, J = 3.8 Hz, 1 H), 7.73 (d, J = 7.6Hz, 2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.34-7.41 (m, 2 H), 7.10 (dd, J =9.0, 2.4 Hz, 1 H), 6.89 (br. S., 1 H), 6.73 (d, J = 3.5 Hz, 1 H), 3.94(s, 2 H), 3.18 (t, J = 5.9 Hz, 2 H), 2.88 (t, J = 5.8 Hz, 2 H). 452.151-E

(MeOD) δ ppm 8.31-8.40 (m, 2 H), 7.91 (d, J = 3.5 Hz, 1 H), 7.75 (dd, J= 8.6, 5.3 Hz, 2 H), 7.40 (d, J = 2.3 Hz, 1 H), 7.20 (t, J = 8.8 Hz, 2H), 7.10 (dd, J = 9.1, 2.3 Hz, 1 H), 6.86 (br. S., 1 H), 6.73 (d, J =3.8 Hz, 1 H), 3.94 (s, 2 H), 3.18 (t, J = 5.8 Hz, 2 H), 2.88 (t, J = 5.7Hz, 2 H). 470.1 51-F

(DMSO-d₆) δ ppm 13.10 (d, J = 2.5 Hz, 1 H), 10.77 (br. S., 1 H), 8.40(s, 1 H), 8.33 (d, J = 9.1 Hz, 1 H), 8.20 (br. S., 1 H), 7.65 (d, J =7.8 Hz, 2 H), 7.52 (q, J = 7.6 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.20(d, J = 16.2 Hz, 1 H), 7.11 (dd, J = 9.1, 2.3 Hz, 2 H), 6.74 (d, J = 3.3Hz, 1 H), 3.82 (s, 2 H), 3.04 (t, J = 5.7 Hz, 2 H), 2.73 (t, J = 5.3 Hz,2 H). 470.2 51-G

(DMSO-d₆) δ ppm 13.09 (br. S., 1 H), 10.76 (br. S., 1 H), 8.40 (s, 1 H),8.33 (d, J = 8.8 Hz, 1 H), 8.20 (d, J = 3.0 Hz, 1 H), 7.72-7.79 (m, 2H), 7.63-7.70 (m, 2 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J = 9.0,2.4 Hz, 1 H), 6.99 (br. S., 1 H), 6.74 (d, J = 3.8 Hz, 1 H), 3.83 (s, 2H), 3.04 (t, J = 5.8 Hz, 2 H), 2.73 (t, J = 5.6 Hz, 2 H). 531.9 51-H

(MeOD) δ ppm 8.32-8.40 (m, 2 H), 7.92 (d, J = 3.7 Hz, 1 H), 7.73 (d, J =8.1 Hz, 2 H), 7.47 (d, J = 8.3 Hz, 2 H), 7.40 (d, J = 2.1 Hz, 1 H), 7.11(dd, J = 9.0, 2.3 Hz, 1 H), 6.96 (br. S., 1 H), 6.74 (d, J = 3.5 Hz, 1H), 3.95 (s, 2 H), 3.19 (t, J = 5.9 Hz, 2 H), 2.89 (t, J = 5.7 Hz, 2 H).486.1 51-I

(DMSO-d₆) δ ppm 13.12 (br. S., 1 H), 10.77 (br. S., 1 H), 8.40 (s, 1 H),8.33 (d, J = 8.8 Hz, 1 H), 8.20 (br. S., 1 H), 7.89 (s, 1 H), 7.77 (d, J= 7.8 Hz, 1 H), 7.38-7.58 (m, 3 H), 7.11 (dd, J = 9.0, 2.4 Hz, 2 H),6.73 (d, J = 3.5 Hz, 1 H), 3.82 (s, 2 H), 3.03 (t, J = 5.8 Hz, 2 H),2.72 (t, J = 5.7 Hz, 2 H). 486.1 51-J

(DMSO-d₆) δ ppm 8.42 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.10 (d, J =3.5 Hz, 1 H), 7.81 (d, J = 7.1 Hz, 2 H), 7.38-7.48 (m, 3 H), 7.31 (t, J= 7.3 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1 H), 6.80 (d, J = 3.5 Hz, 1H), 6.77 (s, 1 H), 3.88 (s, 2 H), 3.81 (s, 3 H), 3.09 (t, J = 5.8 Hz, 2H), 2.76 (br. S., 2 H). 466.1 51-K

(MeOD) δ ppm 8.64 (d, J = 2.0 Hz, 1 H), 8.37 (s, 1 H), 8.33 (d, J = 8.8Hz, 1 H), 8.18 (d, J = 1.0 Hz, 1 H), 8.03 (s, 1 H), 7.92 (d, J = 3.5 Hz,1 H), 7.40 (d, J = 2.3 Hz, 1 H), 7.10 (dd, J = 9.1, 2.3 Hz, 1 H), 6.74(d, J = 3.0 Hz, 1 H), 3.95 (s, 2 H), 3.18 (t, J = 5.9 Hz, 2 H), 2.88 (t,J = 5.8 Hz, 2 H), 2.41 (s, 3 H). 401.1 51-L

(DMSO-d₆) δ ppm 13.65 (br. S., 1 H), 8.40 (s, 1 H), 8.31 (d, J = 8.8 Hz,1 H), 8.17 (d, J = 3.8 Hz, 1 H), 7.42 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J= 9.0, 2.4 Hz, 1 H), 7.00 (br. S., 1 H), 6.73 (d, J = 3.5 Hz, 1 H), 4.33(q, J = 7.2 Hz, 2 H), 3.83 (s, 2 H), 3.04 (t, J = 5.8 Hz, 2 H), 2.73 (t,J = 5.4 Hz, 2 H), 1.33 (t, J = 7.1 Hz, 3 H). 448.1 51-M

Enantiomers separated by chiral HPLC (Ia column, 2:8 hptane/EtOH) M-1:(MeOD) δ ppm 8.32-8.47 (m, 2 H), 7.88 (d, J = 3.8 Hz, 1 H), 7.39 (d, J =2.3 Hz, 1 H) 7.10 (dd, J = 9.1, 2.3 Hz, 1 H), 6.74 (d, J = 3.8 Hz, 1 H),6.51 (s, 1 H), 3.87-4.07 (m, 2 H), 3.05-3.17 (m, 1 H), 3.00 (dd, J =16.9, 3.8 Hz, 1 H), 2.39-2.56 (m, 1 H), 1.34 (d, J = 6.3 Hz, 3 H);Chiral HPLC Rt = 20.6 min M-2: (MeOD) δ ppm 8.29-8.47 (m, 2 H), 7.88 (d,J = 3.8 Hz, 1 H), 7.39 (d, J = 2.3 Hz, 1 H), 7.10 (dd, J = 9.1, 2.3 Hz,1 H), 6.73 (d, J = 3.5 Hz, 1 H), 6.51 (s, 1 H), 3.92-4.05 (m, 2 H),3.05-3.18 (m, 1 H), 3.00 (dd, J = 17.3, 3.7 Hz, 1 H), 2.40-2.58 (m, 1H), 1.34 (d, J = 6.3 Hz, 3 H); Chiral HPLC Rt = 29.7 min. 458.0

EXAMPLE 52 52-A.(±)-6-Methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A solution of4-(1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (150 mg, 0.39 mmol) and THF (5 mL) is cooled to 0°C. To this is added NaH (23.6 mg, 0.59 mmol, 60% in mineral oil)followed by 3-trifluoromethylisocyanate (0.11 mL, 0.79 mmol) and thereaction is allowed to warm to room temperature. After the reaction iscomplete as seen by LCMS the mixture is partitioned between DCM and pH 7buffer solution. The organic layer is removed, dried over anhydrousNa₂SO₄, and concentrated. The crude residue is separated via FCC (5-90%EtOAc/heptane) to give the title compound. MS (ESI) m/z 568.3 (M+1).

52-B. 52-B-1:(−)-(S)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide and 52-B-2:(+)-I-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

A solution of6-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (74 mg, 0.13 mmol), DCM (5 mL), and TFA (5 mL) isstirred at rt for 2 h. At that point the solution is concentrated invacuo and the residue is separated via semi-prep HPLC (C18; 10-100%I/H₂O with 0.1% NH₄OH) to give the racemic title compound. The racemateis then separated via chiral liquid chromatography (Chiralpak AD-column;heptane/EtOH 1:1) to give the two corresponding enantiomers B-1 and B-2.

52-B-1: The compound with R_(t) 5.5 min is assigned as the(+)-(S)-enantiomer; MS (ESI) m/z 468.3 (M+1); ¹H NMR (400 MHz, MeOD) δppm 8.37 (s, 1H) 8.32 (d, J=8.84 Hz, 1H) 8.05 (s, 1H) 7.92 (d, J=3.79Hz, 1H) 7.89 (d, J=8.59 Hz, 1H) 7.56 (t, J=7.96 Hz, 1H) 7.43 (d, J=7.58Hz, 1H) 7.38 (d, J=1.77 Hz, 1H) 7.08 (dd, J=8.97, 1.89 Hz, 1H) 6.72 (d,J=3.54 Hz, 1H) 3.92-4.08 (m, 2H) 3.04-3.15 (m, 1H) 2.98 (dd, J=17.18,3.28 Hz, 1H) 2.46 (dd, J=16.93, 10.61 Hz, 1H) 1.33 (d, J=6.32 Hz, 3H).

52-B-2: The compound with R_(t) 6.7 min is assigned as the (−)-Ienantiomer; MS (ESI) m/z 468.2 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.37(s, 1H) 8.32 (d, J=8.84 Hz, 1H) 8.05 (s, 1H) 7.92 (d, J=3.79 Hz, 1H)7.89 (d, J=8.59 Hz, 1H) 7.56 (t, J=7.96 Hz, 1H) 7.44 (d, J=7.83 Hz, 1H)7.39 (d, J=2.27 Hz, 1H) 7.09 (dd, J=8.97, 2.40 Hz, 1H) 6.73 (d, J=3.79Hz, 1H) 3.89-4.09 (m, 2H) 3.05-3.16 (m, 1H) 2.99 (dd, J=17.18, 379 Hz,1H) 2.47 (dd, J=17.18, 10.36 Hz, 1H) 1.34 (d, J=6.57 Hz, 3H).

The following compounds are prepared with similar method.

52-C.(±)-4-Fluoro-5-(6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 486.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.58 (s, 1H),8.31 (d, J=8.84 Hz, 1H), 8.25 (s, 1H), 8.01-8.17 (m, 2H), 7.76 (t,J=7.96 Hz, 1H), 7.63 (d, J=7.58 Hz, 1H), 7.37 (t, J=8.59 Hz, 1H), 7.00(d, J=3.79 Hz, 1H), 4.20 (d, J=5.05 Hz, 2H), 3.29 (ddd, J=10.48, 6.32,4.17 Hz, 1H), 3.20 (dd, J=17.18, 3.79 Hz, 1H), 2.69 (dd, J=17.18, 10.36Hz, 1H), 1.53 (d, J=6.32 Hz, 3H).

EXAMPLE 53 53-A. 53-A-1:(S)-2-Methyl-5-oxo-1-((S)-1-phenyl-ethyl)-piperidine-4-carboxylic acidethyl ester and 53-A-2:(R)-2-Methyl-5-oxo-1-((S)-1-phenyl-ethyl)-piperidine-4-carboxylic acidethyl ester

Prepared with similar method as Example 50C substituting chiral(−)-(S)-1-phenylethylamine for racemic 1-phenylethylamine in Example50A. The diastereomers A-1 and A-2 are separated via FCC (2.5%EtOAc/heptane).

53-A-1: MS (ESI) m/z 290.2 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm 11.81(s, 1H), 7.18-7.37 (m, 5H), 4.16-4.27 (m, 2H), 3.70 (q, J=6.6 Hz, 1H),3.27-3.38 (m, 1H), 2.82-3.13 (m, 2H), 2.53 (dd, J=15.5, 5.2 Hz, 1H),2.10 (dd, J=15.5, 3.7 Hz, 1H), 1.33 (d, J=6.6 Hz, 3H), 1.30 (t, J=7.1Hz, 3H), 1.05 (d, J=6.6 Hz, 3H).

53-A-2: MS (ESI) m/z 290.2 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm 11.94(s, 1H), 7.19-7.36 (m, 5H), 4.13-4.29 (m, 2H), 3.63 (q, J=6.6 Hz, 1H),3.09-3.52 (m, 2H), 2.94-3.05 (m, 1H), 2.34-2.47 (m, 1H), 1.94 (d, J=15.4Hz, 1H), 1.34 (d, J=6.6 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 0.90 (d, J=6.8Hz, 3H).

53-B. 53-B-1:(S)-4-(1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester and 53-B-2:(R)-4-(1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

Enantiomers 53-B-1 and 53-B-2 are prepared respectively from Example53-A-1 and Example 53-A-2 as described for Example 50-G. 53-B-1: MS(ESI) m/z 381.1 (M+1). 53-B-2: MS (ESI) m/z 381.1 (M+1).

The following compounds are prepared with similar method.

53-C. 53-C-1:(S)-4-(4-Fluoro-1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester and 53-C-2:I-4-(4-Fluoro-1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

Enantiomers 53-C-1 and 53-C-2 are prepared respectively from Example53-A-1 and Example 53-A-2 as described for Example 50-H. 53-C-1: MS(ESI) m/z 399.1 (M+1).

53-C-2: MS (ESI) m/z 397.2 (M−1).

EXAMPLE 54 54-A.(S)-4-{1-[2-tert-Butoxycarbonyl-5-(1-methyl-cyclopropyl)-2H-pyrazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

Sodium hydride (0.024 g, 0.990 mmol; 60% in oil) is added to a solutionof(S)-4-(1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester, Example 53-B-1, (0.126 g, 0.330 mmol) and DMF(7.5 mL) at it. After 5 min3-(1-Methyl-cyclopropyl)-5-phenoxycarbonylamino-pyrazole-1-carboxylicacid tert-butyl ester, Example 5-D, (0.178 g, 0.495 mmol) is then added.After 1 h the mixture is quenched by the addition of saturated aqueousNH₄Cl and then concentrated. The residue is separated directly via FCC(20-70% EtOAc/heptane). MS (ESI) m/z 644.2 (M+1).

54-B.5-((S)-6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-amide

A solution of(S)-4-{1-[2-tert-Butoxycarbonyl-5-(1-methyl-cyclopropyl)-2H-pyrazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (0.212 g, 0.330 mmol), DCM (5 mL), and TFA (2 mL)is stirred at rt for 1 h. The solution is concentrated in vacuo, takenup in MeOH and neutralized by the addition of several drops of aqueousNH₄OH. The residue is then separated via semi-prep HPLC (C18; 10-100%I/H₂O with 0.1% NH₄OH) to give the title compound. MS (ESI) m/z 444.1(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.13 (br. S., 1H), 10.55 (s,1H), 8.40 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.16 (d, J=3.5 Hz, 1H), 7.40(d, J=2.3 Hz, 1H), 7.08 (dd, J=9.1, 2.3 Hz, 1H), 6.70 (d, J=3.8 Hz, 1H),6.30 (s, 1H), 3.76-3.98 (m, 2H), 2.92-3.05 (m, 1H), 2.85 (dd, J=16.5,3.4 Hz, 1H), 2.27-2.40 (m, 1H), 1.41 (s, 3H), 1.22 (d, J=6.3 Hz, 3 H),0.89-0.97 (m, 2H), 0.73-0.82 (m, 2H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 54-C

(MeOD) δ ppm 8.51 (s, 1 H), 8.34 (d, J = 9.0 Hz, 1 H), 7.90 (d, J = 3.8Hz, 1 H), 7.41 (d, J = 2.1 Hz, 1 H), 7.10 (dd, J = 9.0, 2.3 Hz, 1 H),6.72 (d, J = 3.7 Hz, 1 H), 6.28 (s, 1 H), 3.73-3.88 (m, 1 H), 2.86 (dd,J = 17.9, 10.7 Hz, 1 H), 1.59 (d, J = 6.4 Hz, 3 H), 1.46 (s, 3 H),0.92-1.03 (m, 2 H), 0.75-0.88 (m, 2 H). 444.1 54-D

(MeOD) δ ppm 8.52 (s, 1 H), 8.35 (d, J = 9.0 Hz, 1 H), 7.91 (d, J = 3.7Hz, 1 H), 7.41 (d, J = 2.3 Hz, 1 H), 7.10 (dd, J = 9.0, 2.4 Hz, 1 H),6.73 (d, J = 3.7 Hz, 1 H), 6.39 (s, 1 H), 3.72-3.86 (m, 1 H), 2.86 (dd,J = 17.8, 11.0 Hz, 1 H), 2.36-2.52 (m, 3 H), 2.03-2.17 (m, 4 H),1.90-2.02 (m, 2 H), 1.53-1.62 (m, 6 H). 485.1 54-E

(DMSO-d₆) δ ppm 12.21 (br. S., 1 H), 10.56 (s, 1 H), 8.39 (s, 1 H), 8.29(d, J = 9.1 Hz, 1 H), 8.16 (d, J = 3.5 Hz, 1 H), 7.41 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 9.1, 2.3 Hz, 1 H), 6.70 (d, J = 3.5 Hz, 1 H), 6.34 (s,1 H), 3.81 (s, 2 H), 2.87-3.07 (m, 3 H), 2.72 (t, J = 5.6 Hz, 2 H), 1.25(d, J = 6.8 Hz, 6 H). 418.2 54-F

(DMSO-d₆) δ ppm 12.23 (br. S., 1 H), 10.54 (br. S., 1 H), 8.39 (s, 1 H),8.28 (d, J = 9.1 Hz, 1 H), 8.15 (d, J = 3.3 Hz, 1 H), 7.40 (d, J = 2.3Hz, 1 H), 7.08 (dd, J = 9.0, 2.4 Hz, 1 H), 6.69 (d, J = 3.8 Hz, 1 H),6.22 (br. S., 1 H), 3.81 (s, 2 H), 3.03 (t, J = 5.8 Hz, 2 H), 2.72 (t, J= 5.6 Hz, 2 H), 1.82-2.00 (m, 1 H), 0.90-1.01 (m, 2 H), 0.65-0.76 (m, 2H). 416.2 54-G

(MeOD) δ ppm 8.39 (s, 1 H), 8.12 (d, J = 8.84 Hz, 1 H), 7.89 (d, J =3.79 Hz, 1 H), 7.17 (dd, J = 8.84, 7.58 Hz, 1 H), 6.80 (d, J = 3.28 Hz,1 H), 6.30 (br. S., 1 H), 4.02 (d, J = 6.32 Hz, 2 H), 3.13 (ddd, J =10.23, 6.44, 3.79 Hz, 1 H), 3.03 (dd, J = 17.18, 3.28 Hz, 1 H), 2.55(dd, J = 17.18, 10.36 Hz, 1 H), 1.46 (s, 3 H), 1.35 (d, J = 6.32 Hz, 3H), 0.91- 1.04 (m, 2 H), 0.74-0.88 (m, 2 H). 462.1 54-H

(MeOD) δ ppm 8.39 (s, 1 H), 8.12 (d, J = 8.84 Hz, 1 H), 7.89 (d, J =3.79 Hz, 1 H), 7.17 (dd, J = 8.84, 7.58 Hz, 1 H), 6.80 (d, J = 3.28 Hz,1 H), 6.30 (br. S., 1 H), 4.02 (d, J = 6.32 Hz, 2 H), 3.13 (ddd, J =10.23, 6.44, 3.79 Hz, 1 H), 3.03 (dd, J = 17.18, 3.28 Hz, 1 H), 2.55(dd, J = 17.18, 10.36 Hz, 1 H), 1.46 (s, 3 H), 1.35 (d, J = 6.32 Hz, 3H), 0.91- 1.04 (m, 2 H), 0.74-0.88 (m, 2 H). 462.1 54-I

(MeOD) δ ppm 8.39 (s, 1 H), 8.12 (d, J = 8.84 Hz, 1 H), 7.89 (d, J =3.79 Hz, 1 H), 7.17 (dd, J = 8.84, 7.58 Hz, 1 H), 6.80 (d, J = 3.28 Hz,1 H), 6.30 (br. S., 1 H), 4.02 (d, J = 6.32 Hz, 2 H), 3.13 (ddd, J =10.23, 6.44, 3.79 Hz, 1 H), 3.03 (dd, J = 17.18, 3.28 Hz, 1 H), 2.55(dd, J = 17.18, 10.36 Hz, 1 H), 1.46 (s, 3 H), 1.35 (d, J = 6.32 Hz, 3H), 0.91- 1.04 (m, 2 H), 0.74-0.88 (m, 2 H). 462.1 54-J

MeOD) δ ppm 8.38 (s, 1 H), 8.12 (d, J = 8.84 Hz, 1 H), 7.88 (d, J = 3.79Hz, 1 H), 7.17 (dd, J = 8.84, 7.58 Hz, 1 H), 6.80 (d, J = 3.79 Hz, 1 H),6.31 (br. S., 1 H), 3.96 (s, 2 H), 3.19 (t, J = 5.94 Hz, 2 H), 2.91 (t,J = 5.68 Hz, 2 H), 1.46 (s, 3 H) 0.92-1.03 (m, 2 H), 0.76-0.86 (m, 2 H).448.1 54-K

(DMSO-d₆) δ ppm 12.17 (br. S., 1 H), 10.71 (br. S., 1 H), 8.56 (s, 1 H),8.20 (d, J = 3.54 Hz, 1 H), 8.12 (d, J = 8.84 Hz, 1 H), 7.27 (d, J =7.83 Hz, 1 H), 6.84 (d, J = 3.79 Hz, 1 H), 6.29 (s, 1 H), 4.21 (s, 2 H),4.10 (s, 2 H), 1.41 (s, 3 H), 0.85-1.01 (m, 2 H), 0.70- 0.85 (m, 2 H).434.1 54-L

(DMSO-d₆) δ ppm 12.27 (br. S., 1 H) 10.62 (s, 1 H) 8.55 (s, 1 H) 8.30(d, J = 8.84 Hz, 1 H) 8.18 (d, J = 3.54 Hz, 1 H) 7.45 (d, J = 2.27 Hz, 1H) 7.11 (dd, J = 8.84, 2.27 Hz, 1 H) 6.71 (d, J = 3.54 Hz, 1 H) 6.39 (s,1 H) 3.96- 4.26 (m, 4 H) 3.60-3.78 (m, 2 H) 3.46 (ddd, J = 11.49, 8.46,2.78 Hz, 2 H) 2.01 (m, 2 H) 1.63 (m, 2 H) 1.29 (s, 3 H) 460.2 54-M

(DMSO-d₆) δ ppm 12.24 (br. S., 1 H) 10.56 (s, 1 H) 8.55 (s, 1 H) 8.29(d, J = 9.09 Hz, 1 H) 8.17 (d, J = 3.54 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1H) 7.12 (d, J = 9.09 Hz, 1 H) 6.70 (d, J = 3.54 Hz, 1 H) 6.22 (s, 1 H)4.07-4.13 (m, 4 H) 1.91 (dd, J = 13.39, 3.54 Hz, 1 H) 0.95 (dd, J =8.34, 2.27 Hz, 2 H) 0.70-0.74 (m, 2 H) 402.1 54-N

(DMSO-d₆) δ ppm 12.22 (br. S., 1 H) 10.58 (s, 1 H) 8.55 (s, 1 H) 8.30(d, J = 9.09 Hz, 1 H) 8.18 (d, J = 3.79 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1H) 7.11 (dd, J = 8.59, 2.53 Hz, 1 H) 6.71 (d, J = 3.79 Hz, 1 H) 6.34 (s,1 H) 4.07- 4.12 (m, 2 H) 4.09 (d, J = 14.15 Hz, 2H) 2.95 (d, J = 7.07Hz, 1 H) 1.25 (d, J = 6.82 Hz, 6 H). 404.1 54-O

(DMSO-d₆) δ ppm 12.13 (s, 1H) 10.57 (s, 1 H) 8.55 (s, 1 H) 8.29 (d, J =9.09 Hz, 1 H) 8.17 (d, J = 3.79 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1 H) 7.11(dd, J = 9.09, 2.53 Hz, 1 H) 6.71 (d, J = 3.54 Hz, 1 H) 6.29 (s, 1 H)4.09 (d, J = 12.63 Hz, 4H) 1.41 (s, 3 H) 0.91-0.93 (m, 2 H) 0.74-0.78(m, 2 H) 416.2 54-P

(DMSO-d₆) δ ppm 10.11 (s, 1 H) 8.54 (s, 1 H) 8.43 (d, J = 9.09 Hz, 1 H)8.19 (d, J = 3.79 Hz, 1 H) 7.51 (d, J = 2.53 Hz, 2 H) 7.22 (dd, J =8.97, 2.40 Hz, 1 H) 6.76-6.90 (m, 2 H) 4.21 (t, J = 2.15 Hz, 2 H) 4.14(t, J = 2.27 Hz, 2 H) 3.48 (s, 2 H) 2.78-2.82 (m, 2 H) 1.41- 1.52 (m, 5H) 430.3 54-Q

(DMSO-d₆) δ ppm 12.13 (br. S., 1 H), 10.55 (s, 1 H), 8.40 (s, 1 H), 8.29(d, J = 8.8 Hz, 1 H), 8.16 (d, J = 3.8 Hz, 1 H), 7.41 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 9.0, 2.4 Hz, 1 H), 6.70 (d, J = 3.5 Hz, 1 H), 6.29 (s,1 H), 3.84 (s, 2 H), 3.05 (t, J = 5.8 Hz, 2 H), 2.69-2.78 (m, 2 H), 1.41(s, 3 H), 1.25 (br. S., 2 H), 0.89- 0.97 (m, 2 H) 430.2 54-R

(DMSO-d₆) δ ppm 10.56 (s, 1 H), 8.40 (s, 1 H), 8.29 (d, J = 9.1 Hz, 1H), 8.16 (d, J = 3.8 Hz, 1 H), 7.40 (d, J = 2.3 Hz, 1 H), 7.08 (dd, J =9.0, 2.4 Hz, 1 H), 6.70 (d, J = 3.5 Hz, 1 H), 6.34 (br. S., 1 H),3.79-3.98 (m, 2 H), 2.89- 3.04 (m, 2 H), 2.85 (dd, J = 16.8, 3.4 Hz, 1H), 2.27-2.39 (m, 1 H), 1.17-1.30 (m, 9 H) 432.2 54-S

(DMSO-d₆) δ ppm 10.56 (s, 1 H), 8.40 (s, 1 H), 8.29 (d, J = 9.1 Hz, 1H), 8.16 (d, J = 3.5 Hz, 1 H), 7.40 (d, J = 2.5 Hz, 1 H), 7.08 (dd, J =9.0, 2.4 Hz, 1 H), 6.70 (d, J = 3.8 Hz, 1 H), 6.34 (s, 1 H), 3.77-3.98(m, 2 H), 2.90- 3.03 (m, 2 H), 2.85 (dd, J = 16.9, 3.5 Hz, 1 H),2.27-2.39 (m, 1 H), 1.16-1.33 (m, 9 H) 432.2 54-T

(DMSO-d₆) δ ppm 12.79 (br. S., 1 H), 10.72 (br. S., 1 H), 8.40 (s, 1 H),8.29 (d, J = 9.0 Hz, 1 H), 8.16 (br. S., 1 H), 7.42 (d, J = 1.8 Hz, 1H), 7.10 (d, J = 10.9 Hz, 1 H), 6.60-6.77 (m, 2 H), 3.84 (br. S., 2 H),3.06 (br. S., 2 H), 2.74 (br. S., 2 H), 1.39 (br. S., 2 H), 1.29 (br.S., 2 H) 484.1 54-U

(MeOD) δ ppm 8.53 (s, 1 H) 8.33 (d, J = 8.84 Hz, 1 H) 7.90 (d, J = 3.79Hz, 1 H) 7.67 (d, J = 2.53 Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1 H) 7.11 (dd,J = 8.97, 2.40 Hz, 1 H) 6.71 (d, J = 3.79 Hz, 1 H) 6.55 (d, J = 2.27 Hz,1 H) 4.19 (d, J = 7.83 Hz, 4 H) 1.59 (s, 9 H) 418.1 54-V

(DMSO-d₆) δ ppm 8.40 (s, 1 H) 8.30 (d, J = 9.09 Hz, 1 H) 8.20 (d, J =3.79 Hz, 1 H) 7.78 (d, J = 2.27 Hz, 1 H) 7.40 (d, J = 2.53 Hz, 1 H) 7.08(dd, J = 8.97, 2.40 Hz, 1 H) 6.70 (d, J = 3.79 Hz, 1 H) 6.52 (d, J =2.53 Hz, 1 H) 3.87 (d, J = 6.82 Hz, 2 H) 2.96 (ddd, J = 10.36, 6.06,4.29 Hz, 1 H) 2.85 (dd, J = 16.80, 3.92 Hz, 1 H) 2.33 (dd, J = 16.42,9.60 Hz, 1 H) 1.54 (s, 9 H) 1.21 (d, J = 6.32 Hz, 3 H) 446.1 54-W

(DMSO-d₆) δ ppm 10.57 (s, 1 H) 8.39 (s, 1 H) 8.28 (d, J = 8.84 Hz, 1 H)8.15 (d, J = 3.79 Hz, 1 H) 7.41 (d, J = 2.27 Hz, 1 H) 7.08 (dd, J =8.97, 2.40 Hz, 1 H) 6.70 (d, J = 3.79 Hz, 1 H) 6.34 (s, 1 H) 3.81 (s, 2H) 3.68 (s, 3 H) 3.03 (t, J = 5.81 Hz, 2 H) 2.72 (t, J = 5.68 Hz, 2 H)2.27 (s, 3 H) 404.0 54-X

(DMSO-d₆) δ ppm 10.70 (s, 1 H) 8.39 (s, 1 H) 8.30 (d, J = 8.97 Hz, 1 H)8.20 (d, J = 3.54 Hz, 1 H) 7.78 (d, J = 2.27 Hz, 1 H) 7.41 (d, J = 2.53Hz, 1 H) 7.08 (dd, J = 8.97, 2.40 Hz, 1 H) 6.70 (d, J = 3.03 Hz, 1 H)6.52 (d, J = 2.53 Hz, 1 H) 3.81 (s, 2 H) 3.03 (t, J = 5.94 Hz, 2 H) 2.72(t, J = 5.68 Hz, 2 H) 1.54 (s, 9 H) 432.0 54-Y

(MeOD) δ ppm 8.53 (s, 1 H) 8.32 (d, J = 8.84 Hz, 1 H) 7.88 (d, J = 3.79Hz, 1 H), 7.42 (d, J = 2.53 Hz, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1 H)6.71 (d, J = 3.54 Hz, 1 H) 6.32 (s, 1 H) 4.51 (qd, J = 6.61, 6.44 Hz, 1H) 4.19 (d, J = 6.06 Hz, 4 H) 2.32 (s, 3 H) 1.44 (d, J = 6.82 Hz, 6 H)418.0 54-Z

(DMSO-d₆) δ ppm 10.62 (s, 1 H) 8.39 (s, 1 H) 8.29 (d, J = 8.84 Hz, 1 H)8.19 (d, J = 3.79 Hz, 1 H) 7.40 (d, J = 2.78 Hz, 1 H) 7.08 (dd, J =8.97, 2.40 Hz, 1 H) 6.69 (d, J = 3.03 Hz, 1H) 6.33 (s, 1 H) 4.48 (quin,J = 6.57 Hz, 1 H) 3.81 (s, 2 H) 3.02 (t, J = 5.81 Hz, 2 H) 2.72 (t, J =5.56 Hz, 2 H) 2.29 (s, 3 H) 1.38 (d, J = 6.57 Hz, 6 H) 432.0 54-AA

(DMSO-d₆) δ ppm 10.72 (s, 1 H) 8.39 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H)8.19 (d, J = 3.79 Hz, 1 H) 7.73 (d, J = 2.27 Hz, 1 H) 7.41 (d, J = 2.27Hz, 1 H) 7.08 (dd, J = 8.97, 2.40 Hz, 1 H) 6.70 (d, J = 3.79 Hz, 1 H)6.51 (d, J = 2.27 Hz, 1 H) 4.45 (dt, J = 13.33, 6.60 Hz, 1 H) 3.81 (s, 2H) 3.03 (t, J = 5.81 Hz, 2 H) 2.72 (t, J = 5.68 Hz, 2 H) 1.44 (d, J =6.57 Hz, 6 H) 418.0 54-AB

(DMSO-d₆) δ ppm 10.58 (d, J = 1.26 Hz, 1 H) 8.55 (s, 1 H) 8.30 (d, J =8.59 Hz, 1 H) 8.16 (d, J = 3.54 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1 H) 7.11(dd, J = 8.97, 2.40 Hz, 1 H) 6.70 (d, J = 4.04 Hz, 1 H) 6.34 (s, 1 H)4.06-4.11 (m, 4H) 3.68 (s, 3 H) 2.27 (s, 3 H) 390.0 54-AC

(MeOD) δ ppm 8.53 (s, 1 H) 8.33 (d, J = 8.84 Hz, 1 H) 7.90 (d, J = 3.54Hz, 1 H) 7.60 (d, J = 2.27 Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1 H) 7.12 (dd,J = 8.97, 2.40 Hz, 1 H) 6.71 (d, J = 3.54 Hz, 1 H) 6.53 (d, J = 2.53 Hz,1 H) 4.46 (dt, J = 13.39, 6.69 Hz, 1 H) 4.19 (d, J = 6.82 Hz, 4 H) 1.50(d, J = 6.82 Hz, 6 H) 404.1 54-AD

(MeOD) δ ppm 12.80 (br. S., 1 H) 10.74 (s, 1 H) 8.55 (s, 1 H) 8.30 (d, J= 8.84 Hz, 1 H) 8.18 (d, J = 3.28 Hz, 1 H) 7.45 (s, 1 H) 7.13 (s, 1 H)6.72 (d, J = 3.28 Hz, 1 H) 6.67 (s, 1 H) 4.08 (d, J = 1.52 Hz, 2 H)4.06-4.13 (m, 2 H) 1.40 (br. S., 2 H) 1.30 (br. S., 2 H) 470.9

EXAMPLE 55 55-A.4-[1-(5-Trifluoromethyl-pyridin-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

A solution of4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (92 mg, 0.25 mmol) and THF (5 mL) is treated withNaH (20 mg, 0.50 mmol, 60% mineral oil) and then Example 13-A (304 mg,0.75 mmol) is added. After 24 h, the reaction is concentrated in vacuoand partitioned between DCM and water. The organic layer is removed,dried, and concentrated. The crude residue is separated via FCC (5-90%EtOAc/heptane) to give the title compound. MS (ESI) m/z 555.1 (M+1).

55-B.5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-trifluoromethyl-pyridin-3-yl)-amide

A solution of4-[1-(5-trifluoromethyl-pyridin-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (47 mg, 85 umol), DCM (2 mL), and TEA (2 mL) isstirred at rt for 2 h. The solution is then concentrated and the residueis separated via semi-prep HPLC (C18; 10-100% I/H₂O with 0.1% NH₄OH) togive the title compound. MS (ESI) m/z 455.1 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.54 (s, 1H), 9.11 (d, J=2.3 Hz, 1H), 8.72 (s, 1H), 8.50(t, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.11 (d, J=3.8Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 6.81 (d,J=3.5 Hz, 1H), 3.82 (s, 2H), 3.04 (t, J=5.8 Hz, 2H), 2.73 (t, J=5.6 Hz,2H).

The following compounds are prepared with similar method.

55-C.(±)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-trifluoromethyl-pyridin-3-yl)-amide

MS (ESI) m/z 469.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 9.07 (d, J=2.3Hz, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.32-8.42 (m, 2H), 7.95 (d, J=3.5Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.12 (dd, J=9.1, 2.3 Hz, 1H), 6.77 (d,J=3.8 Hz, 1H), 4.05 (d, J=7.6 Hz, 2H), 3.18 (ddd, J=10.5, 6.3, 4.2 Hz,1H), 3.04 (dd, J=17.4, 3.8 Hz, 1H), 2.52 (dd, J=17.4, 10.4 Hz, 1H), 1.37(d, J=6.3 Hz, 3H).

EXAMPLE 56 56-A.4-[1-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

To a solution of4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester, Example 31-C, (1.1 g, 3.00 mmol) in THF (50 ml),NaH (0.360 g, 9.01 mmol) is added under nitrogen at 0° C. and theresulting mixture is stirred for 1 h. Then a solution of(5-tert-butyl-isoxazol-3-yl)-carbamic acid phenyl ester (1.56 g, 6.00mmol) in THF is added. The resulting mixture is stirred at 0° C. for 1h. The mixture is allowed to warm to rt and stir overnight. The mixtureis then quenched with sat aq ammonium chloride solution and thenextracted with EtOAc (2×). The combined organic layers are washed withbrine, dried over anhydrous sodium sulfate, filtered, and condensed. Theresidue is then separated by FCC (0-70% EtOAc/Heptane) to provide thetitle compound. MS (ESI) m/z 533.1 (M+1).

56-B.5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

4-[1-(5-Tert-Butyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (1.4 g) is stirred in the mixture of DCM (200 ml)and TFA (2 ml) overnight. After removal of solvents, the residue isneutralized with sat aqueous sodium bicarbonate and extracted with EtOAc(3×). Combined organic layers are washed with water, brine, dried withNa₂SO₄, filtered, and condensed. The residue is then separated by FCC(0-10%, 2 M NH₃ in MeOH/DCM) to provide the title compound. MS (ESI) m/z432.9 (M+1);

¹H NMR (400 MHz, MeOD) δ ppm 8.37 (s, 1H) 8.33 (d, J=8.84 Hz, 1H) 7.88(d, J=3.79 Hz, 1H) 7.38 (d, J=2.02 Hz, 1H) 7.10 (dd, J=8.84, 2.27 Hz,1H) 6.72 (d, J=3.79 Hz, 1H) 6.65 (s, 1H) 3.94 (s, 2H) 3.17 (t, J=5.94Hz, 2H) 2.87 (t, J=5.68 Hz, 2H) 1.38 (s, 9H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 56-C

(MeOD) δ ppm 8.35 (br. S., 1 H) 7.48 (d, J = 8.84 Hz, 1 H) 7.04 (t, J =6.69 Hz, 1 H) 6.66 (s, 1 H) 6.49 (br. S., 1 H) 3.93 (br. S., 2 H) 3.15(br. S., 2 H) 2.87 (br. S., 2 H) 2.58 (br. S., 3 H) 1.38 (s, 9 H). 464.956-D

(MeOD) δ ppm 8.35-8.39 (m, 2 H) 7.90 (d, J = 3.79 Hz, 1 H) 7.38 (d, J =2.27 Hz, 1 H) 7.09 (s, 1 H) 6.71 (d, J = 3.79 Hz, 1 H) 6.37 (s, 1 H)4.00 (s, 2 H) 3.21-3.25 (m, 2 H) 2.91 (s, 2 H) 1.36 (s, 9 H). 433.0 56-E

(MeOD) δ ppm 8.37 (s, 1 H), 8.34 (d, J = 8.8 Hz, 1 H), 7.90 (d, J = 3.8Hz, 1 H), 7.39 (d, J = 2.3 Hz, 1 H), 7.10 (dd, J = 9.0, 2.4 Hz, 1 H),6.73 (d, J = 3.8 Hz, 1 H), 6.65 (s, 1 H), 3.90- 4.08 (m, 2 H), 3.05-3.16(m, 1 H), 3.00 (dd, J = 17.1, 3.7 Hz, 1 H), 2.48 (dd, J = 17.1, 10.7 Hz,1 H), 1.39 (s, 9 H), 1.34 (d, J = 6.3 Hz, 3 H). 447.1 56-F

(DMSO-d₆) δ ppm 8.40 (s, 1 H) 8.29 (d, J = 9.09 Hz, 1 H) 8.15 (d, J =3.28 Hz, 1 H) 7.43 (d, J = 1.26 Hz, 1 H) 7.11 (dd, J = 8.72, 1.39 Hz, 1H) 6.75 (d, J = 3.03 Hz, 1 H) 6.68 (s, 1 H) 3.79- 3.98 (m, 2 H)2.91-3.05 (m, 1 H) 2.85 (d, J = 16.17 Hz, 1 H) 2.34 (dd, J = 16.17, 9.60Hz, 1 H) 1.34 (s, 9 H) 1.21 (d, J = 6.32 Hz, 3 H). R_(t) 8.92 min(Chiralpak IA column- MeCN/EtOH 4:6) 447.2 56-G

(DMSO-d₆) δ ppm 8.40 (s, 1 H) 8.29 (d, J = 9.09 Hz, 1 H) 8.15 (d, J =3.79 Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1H) 6.75 (d, J = 3.79 Hz, 1 H) 6.68 (s, 1 H) 3.81- 3.95 (m, 2 H)2.90-3.02 (m, 1 H) 2.85 (dd, J = 17.05, 3.66 Hz, 1 H) 2.34 (dd, J =16.67, 9.85 Hz, 1 H) 1.34 (s, 9 H) 1.21 (d, J = 6.32 Hz, 3 H). R_(t)11.77 min (Chiralpak IA column- MeCN/EtOH 4:6) 447.1 56-H

(DMSO-d₆) δ ppm 8.41 (s, 1 H), 8.18 (d, J = 3.8 Hz, 1 H), 8.12 (d, J =9.1 Hz, 1 H), 7.21-7.32 (m, 1 H), 6.87 (d, J = 3.8 Hz, 1 H), 6.67 (s, 1H), 3.85 (s, 2 H), 3.06 (t, J = 5.8 Hz, 2 H), 2.76 (t, J = 5.7 Hz, 2 H),1.34 (s, 9 H). 451.1 56-I

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.29 (d, J = 9.1 Hz, 1 H), 8.15 (d, J =3.5 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1 H), 6.69 (d, J = 0.8 Hz, 1 H), 3.79-3.96 (m,2 H), 3.04-3.18 (m, 1 H), 2.90-3.03 (m, 1 H), 2.85 (dd, J = 16.8, 3.4Hz, 1 H), 2.33 (dd, J = 16.7, 10.4 Hz, 1 H), 1.29 (d, J = 6.8 Hz, 6 H),1.21 (d, J = 6.3 Hz, 3 H). 433.1 56-J

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.28 (d, J = 9.1 Hz, 1 H), 8.14 (d, J =3.5 Hz, 1 H), 7.42 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J = 8.8, 2.3 Hz, 1H), 6.74 (d, J = 3.8 Hz, 1 H), 6.65 (s, 1 H), 3.80- 3.95 (m, 2 H),2.90-3.03 (m, 1 H), 2.84 (dd, J = 16.9, 3.5 Hz, 1 H), 2.33 (dd, J =16.7, 10.4 Hz, 1 H), 2.12-2.21 (m, 1 H), 1.21 (d, J = 6.1 Hz, 3 H),1.03-1.12 (m, 2 H), 0.91-0.97 (m, 2 H). 431.0 56-K

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.16 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.11 (dd, J = 8.8, 2.3 Hz, 1H), 6.72-6.78 (m, 2 H), 3.81-3.95 (m, 2 H), 3.64- 3.76 (m, 1 H),2.90-3.03 (m, 1 H), 2.85 (dd, J = 16.5, 3.4 Hz, 1 H), 2.31-2.41 (m, 3H), 2.18- 2.31 (m, 2 H), 1.98-2.12 (m, 1 H), 1.87- 1.98 (m, 1 H),1.18-1.24 (m, 3 H). 445.1 56-L

(DMSO-d₆) δ ppm 8.39 (s, 1 H), 8.30 (d, J = 8.8 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.71-6.78 (m, 2 H), 3.82 (s, 2 H), 3.63-3.75 (m, 1 H), 3.03 (t, J =5.8 Hz, 2 H), 2.72 (t, J = 5.7 Hz, 2 H), 2.30-2.43 (m, 2 H), 2.17-2.31(m, 2 H), 1.99-2.11 (m, 1 H), 1.86-1.99 (m, 1 H). 431.3 56-M

(DMSO-d₆) δ ppm 8.39 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 8.14 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1 H), 6.65 (s, 1 H), 3.82 (s, 2 H), 3.03 (t, J= 5.8 Hz, 2 H), 2.72 (t, J = 5.7 Hz, 2 H), 2.12-2.22 (m, 1 H), 1.04-1.13(m, 2 H), 0.89-0.98 (m, 2 H). 417.2 56-N

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.16 (d, J =3.5 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.75 (d, J = 3.8 Hz, 1 H), 6.69 (d, J = 0.8 Hz, 1 H), 3.82 (s, 2 H),3.06-3.16 (m, 1 H), 3.03 (t, J = 5.8 Hz, 2 H), 2.72 (t, J = 5.6 Hz, 2H), 1.29 (d, J = 7.1 Hz, 6 H). 419.0 56-O

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.15 (d, J =3.5 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1H), 6.75 (d, J = 3.8 Hz, 1 H), 6.67 (s, 1 H), 3.82 (s, 2 H), 3.03 (t, J= 5.8 Hz, 2 H), 2.72 (t, J = 5.7 Hz, 2 H), 1.46(s, 3H), 1.12-1.18 (m,2H), 0.90- 0.97 (m, 2 H). 431.2 56-P

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1 H), 6.66 (s, 1 H), 3.80- 3.95 (m, 2 H),2.91-3.03 (m, 1 H), 2.85 (dd, J = 16.9, 3.5 Hz, 1 H), 2.34 (dd, J =16.8, 10.2 Hz, 1 H), 1.46 (s, 3 H), 1.21 (d, J = 6.3 Hz, 3 H), 1.12-1.17(m, 2 H), 0.91-0.96 (m, 2 H). 445.3 56-Q

(DMSO-d₆) δ ppm 8.42 (s, 1 H), 8.19 (d, J = 3.79 Hz, 1 H), 8.12 (d, J =8.84 Hz, 1 H), 7.27 (d, J = 7.58 Hz, 1 H), 6.87 (d, J = 3.79 Hz, 1 H),6.67 (s, 1 H), 3.90 (d, J = 7.07 Hz, 2 H), 3.00 (ddd, J = 10.23, 6.44,3.79 Hz, 1 H), 2.86 (dd, J = 17.18, 3.28 Hz, 1 H), 2.40 (dd, J = 17.18,10.36 Hz, 1 H), 1.34 (s, 9 H), 1.22 (d, J = 6.32 Hz, 3 H). 465.1 56-R

(DMSO-d₆) δ ppm 8.42 (s, 1 H), 8.19 (d, J = 3.79 Hz, 1 H), 8.12 (d, J =8.84 Hz, 1 H), 7.27 (d, J = 7.58 Hz, 1 H), 6.87 (d, J = 3.79 Hz, 1 H),6.67 (s, 1 H), 3.90 (d, J = 7.07 Hz, 2 H), 3.00 (ddd, J = 10.23, 6.44,3.79 Hz, 1 H), 2.86 (dd, J = 17.18, 3.28 Hz, 1 H), 2.40 (dd, J = 17.18,10.36 Hz, 1 H), 1.34 (s, 9 H), 1.22 (d, J = 6.32 Hz, 3 H). 465.1 56-S

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.27 (d, J = 9.1 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.74 (d, J = 3.3 Hz, 1 H), 6.65 (s, 1 H), 3.79- 3.95 (m, 2 H),2.90-3.01 (m, 1 H), 2.85 (dd, J = 16.9, 3.5 Hz, 1 H), 2.34 (dd, J =16.8, 10.2 Hz, 1 H), 2.12-2.23 (m, 1 H), 1.21 (d, J = 6.3 Hz, 3 H),1.05-1.12 (m, 2 H), 0.91-0.97 (m, 2 H) 431.2 56-T

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.4 Hz, 1 H), 7.11 (dd, J = 9.0, 2.3 Hz, 1H), 6.75 (d, J = 3.8 Hz, 1 H), 6.65 (s, 1 H), 3.78- 3.95 (m, 2 H),2.91-3.04 (m, 1 H), 2.80-2.90 (m, 1 H), 2.27-2.40 (m, 1 H), 2.12-2.22(m, 1 H), 1.21 (d, J = 6.3 Hz, 3 H), 1.04-1.12 (m, 2 H), 0.90-0.98 (m, 2H) 431.0 56-U

(DMSO-d₆) δ ppm 8.41 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1H), 7.04 (s, 1 H), 6.75 (d, J = 3.5 Hz, 1 H), 3.77- 3.96 (m, 2 H),2.95-3.05 (m, 1 H), 2.86 (dd, J = 17.1, 3.4 Hz, 1 H), 2.32 (dd, J = 3.9,1.9 Hz, 1 H), 1.50-1.60 (m, 4 H), 1.22 (d, J = 6.3 Hz, 3 H) 499.1 56-V

(DMSO-d₆) δ ppm 1.21 (d, J = 6.3 Hz, 3 H), 1.29 (d, J = 6.8 Hz, 6 H),2.27-2.40 (m, 1 H), 2.85 (dd, J = 16.9, 3.5 Hz, 1 H), 2.92-3.02 (m, 1H), 3.05- 3.18 (m, 1 H), 3.80-3.95 (m, 2 H), 6.69 (s, 1 H), 6.75 (d, J =3.8 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 3.8 Hz, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 8.40 (s, 1 H)433.2 56-W

(DMSO-d₆) δ ppm 0.90-0.97 (m, 2 H), 1.11- 1.18 (m, 2 H), 1.21 (d, J =6.3 Hz, 3 H), 1.46 (s, 3 H), 2.34 (dd, J = 16.8, 10.2 Hz, 1 H), 2.85(dd, J = 16.9, 3.5 Hz, 1 H), 2.90-3.03 (m, 1 H), 3.79- 3.96 (m, 2 H),6.67 (s, 1 H), 6.75 (d, J = 3.8 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1 H), 8.16 (d, J = 3.7 Hz, 1 H), 8.28 (d, J =9.0 Hz, 1 H), 8.40 (s, 1 H) 445.2 56-X

(DMSO-d₆) δ ppm 8.41 (s, 1 H), 8.27 (d, J = 9.1 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.74 (d, J = 3.8 Hz, 1 H), 6.65 (s, 1 H), 3.92 (s, 2 H), 3.06 (t, J= 5.7 Hz, 2 H), 2.74 (t, J = 5.7 Hz, 2 H), 2.12-2.22 (m, 1 H), 1.04-1.13(m, 2 H), 0.90-0.98 (m, 2 H). 417.1 56-Y

(DMSO-d₆) δ ppm 8.44 (s, 1 H), 8.29 (d, J = 9.1 Hz, 1 H), 8.16 (d, J =3.8 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1H), 6.76 (d, J = 3.8 Hz, 1 H), 6.68 (s, 1 H), 4.00 (s, 2 H), 3.14 (appt, J = 5.7 Hz, 2 H), 2.79 (app t, J = 5.7 Hz, 2 H), 1.34 (s, 9 H) 433.156-X

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.30 (d, J = 8.8 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1H), 7.04 (s, 1 H), 6.75 (d, J = 3.8 Hz, 1 H), 3.84 (s, 2 H), 3.05 (t, J= 5.8 Hz, 2 H), 2.73 (t, J = 5.7 Hz, 2 H), 1.46-1.61 (m, 4 H) 485.1 56-Y

(DMSO-d₆) δ ppm 8.40 (s, 1 H), 8.30 (d, J = 8.8 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.12 (dd, J = 9.0, 2.4 Hz, 1H), 7.04 (s, 1 H), 6.75 (d, J = 3.8 Hz, 1 H), 3.84 (s, 2 H), 3.05 (t, J= 5.8 Hz, 2 H), 2.73 (t, J = 5.7 Hz, 2 H), 1.46-1.61 (m, 4H) 485.1 56-Z

(DMSO-d₆) δ ppm 10.58 (s, 1 H) 8.39 (s, 1 H) 8.27 (d, J = 9.09 Hz, 1 H)8.14 (d, J = 3.79 Hz, 1 H) 7.40 (d, J = 2.02 Hz, 1 H) 7.07(dd, J = 8.97,2.40 Hz, 1 H) 6.70 (d, J = 3.79 Hz, 1 H) 6.16 (s, 1 H) 3.87 (d, J = 6.32Hz, 2 H) 3.75-3.82 (m, 3 H) 2.94-2.96 (m, 1 H) 2.82-2.87 (m, 1H) 2.33(ddd, J = 3.85, 1.83, 1.64 Hz, 1 H) 1.85-1.96 (m, 1 H) 1.21 (d, J = 6.32Hz, 3 H) 0.92-1.02 (m, 2 H) 0.62-0.70 (m, 2 H) 444.1 56-AA

(DMSO-d₆) δ ppm 8.40 (s, 1 H) 8.29 (d, J = 9.09 Hz, 1 H) 8.17 (d, J =3.79 Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1 H) 7.07-7.12 (m, 2 H) 6.74 (d, J =3.79 Hz, 1 H) 3.95 (s, 3 H) 3.87 (d, J = 6.06 Hz, 2 H) 2.92-3.00 (m, 1H) 2.85 (dd, J = 16.93, 3.54 Hz, 1 H) 2.33 (dd, J = 16.55, 10.48 Hz, 1H) 1.21 (d, J = 6.06 Hz, 3 H) 472.0

EXAMPLE 57 57-A.5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

Tert-butyl4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (127mg, 0.360 mmol) is dissolved in THF (8 mL), flushed with nitrogen andcooled to 0° C. Sodium hydride (23 mg, 0.575 mmol, 60% in mineral oil)is added and the mixture is stirred for 10 minutes. Phenyl5-tert-butylisoxazol-3-ylcarbamate (140 mg, 0.538 mmol) is added neatand the reaction is allowed to stir at room temperature overnight. Thereaction is cooled in an ice bath and quenched with a saturated solutionof ammonium chloride (100 mL). The mixture is then diluted with ethylacetate and the product is extracted (2×100 mL EtOAc). The organiclayers are combined, dried and concentrated to a brown oil that isdissolved in 10 mL of DCM and cooled in an ice bath and 10 mL of TFA isadded. Following completion of the reaction the DCM and TFA are removedand ethyl acetate is added to the residue along with ammonium hydroxideto quench the remaining TFA. The mixture is diluted with water andextracted with ethyl acetate (2×50 mL). The organic layers are removed,dried, and concentrated. The residue is absorbed onto silica andseparated via FCC (0-6% Methanol/DCM) to obtainN-(5-tert-butylisoxazol-3-yl)-5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide.MS (ESI) m/z 419.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (s, 1H)8.29 (d, J=8.84 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.47 (d, J=2.27 Hz, 1H)7.15 (dd, J=8.97, 2.40 Hz, 1H) 6.76 (d, J=3.28 Hz, 1H) 6.68 (s, 1H)4.07-4.14 (m, 4H) 1.34 (s, 9H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 57-B

(DMSO-d₆) δ ppm 8.61 (s, 1 H) 8.42 (d, J = 9.09 Hz, 1 H) 8.11 (d, J =3.79 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1 H) 7.11 (dd, J = 9.22, 2.40 Hz, 1H) 6.67 (d, J = 3.54 Hz, 1 H) 6.22 (s, 1 H) 4.25 (br. S., 4 H) 1.28 (s,9 H). 419.9 57-C

(MeOD) δ ppm 8.52 (s, 1 H), 7.70 (d, J = 8.84 Hz, 1 H), 7.29 (d, J =2.27 Hz, 1 H), 7.02 (dd, J = 8.84, 2.27 Hz, 1 H), 6.65 (s, 1 H), 6.44(s, 1 H), 4.19 (d, J = 5.56 Hz, 2 H), 4.18 (s, 2 H), 2.60 (s, 3 H), 1.39(s, 9 H). 433.2 57-D

(DMSO-d₆) δ ppm 8.58 (s, 1 H) 8.35 (d, J = 9.09 Hz, 1 H) 8.19 (d, J =3.54 Hz, 1 H) 8.01 (d, J = 7.83 Hz, 1 H) 7.72-7.75 (m, 1 H) 7.68 (dd, J= 6.82, 1.26 Hz, 1 H) 7.50 (d, J = 2.27 Hz, 1 H) 7.39 (t, J = 7.58 Hz, 1H) 7.16 (dd, J = 8.97, 2.40 Hz, 1 H) 6.79 (d, J = 3.79 Hz, 1 H) 4.12 (d,J = 14.91 Hz, 4 H). 413.1 57-E

(DMSO-d₆) δ ppm 8.68 (s, 1 H) 8.58 (d, J = 8.84 Hz, 1 H) 8.13 (d, J =3.54 Hz, 1 H) 7.88 (dd, J = 8.84, 5.56 Hz, 2 H) 7.42 (d, J = 2.53 Hz, 1H) 7.32 (dd, J = 8.84, 4.55 Hz, 2 H) 7.08 (dd, J = 8.97, 2.40 Hz, 1 H)6.60 (d, J = 3.54 Hz, 1 H) 6.58 (s, 1 H) 4.38 (d, J = 5.31 Hz, 4 H).457.1 57-F

(DMSO-d₆) δ ppm 8.68 (s, 1 H) 8.58 (d, J = 9.35 Hz, 1 H) 8.13 (d, J =3.54 Hz, 1 H) 7.83 (d, J = 8.08 Hz, 2 H) 7.42-7.52 (m, 5 H) 7.09 (dd, J= 8.97, 1.89 Hz, 1 H) 6.61 (d, J = 3.54 Hz, 1 H) 6.59 (s, 1 H) 4.36 (d,J = 3.54 Hz, 4 H). 439.1 57-G

(DMSO-d₆) δ ppm 8.62 (s, 1 H) 8.44 (d, J = 8.84 Hz, 1 H) 8.11 (d, J =3.54 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.11 (dd, J = 9.09, 2.53 Hz, 1H) 6.67 (d, J = 3.54 Hz, 1 H) 6.17 (s, 1 H) 4.26 (d, J = 5.56 Hz, 4 H)2.88-2.96 (m, 1 H) 1.23 (d, J = 6.82 Hz, 6 H). 405.1 57-H

(DMSO-d₆) δ ppm 8.62 (s, 1 H) 8.43 (d, J = 8.84 Hz, 1 H) 8.11 (d, J =3.79 Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1 H) 7.10 (dd, J = 8.84, 2.53 Hz, 1H) 6.66 (d, J = 4.04 Hz, 1 H) 6.11 (s, 1 H) 4.25 (br. S., 3 H) 4.08 (br.S., 1 H) 2.41-2.45 (m, 2 H) 1.96 (dd, J = 13.52, 6.69 Hz, 1 H) 0.94 (d,J = 6.57 Hz, 6 H). 419.0 57-I

(MeOD) δ ppm 8.54 (s, 1 H) 8.39 (d, J = 9.09 Hz, 1 H) 7.93 (d, J = 3.79Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1 H)6.75 (d, J = 3.79 Hz, 1 H) 6.32 (s, 1 H) 4.26 (br. S., 4 H) 2.56 (s, 2H) 0.98-1.04 (m, 9 H). 433.1 57-J

(DMSO-d₆) δ ppm 8.62 (s, 1 H) 8.42 (d, J = 8.84 Hz, 1 H) 8.10 (d, J =3.79 Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1H) 6.67 (d, J = 3.79 Hz, 1 H) 6.14 (s, 1 H) 4.22-4.29 (m, 4 H) 2.63 (s,1 H) 1.89 (d, J = 12.13 Hz, 2H) 1.73-1.79 (m, 2 H) 1.23-1.50 (m, 6 H).445.0 57-K

(DMSO-d₆) δ ppm 8.58 (s, 1 H) 8.51 (d, J = 8.08 Hz, 1 H) 8.06 (d, J =3.54 Hz, 1 H) 7.37 (d, J = 2.78 Hz, 1 H) 7.04 (d, J = 9.09 Hz, 1 H) 6.56(s, 1 H) 5.86 (s, 1 H) 4.15 (s, 4H) 1.37 (s, 3 H) 0.92 (m, 2 H) 0.77 (m,2 H) 417.1 57-L

(TFA salt) (DMSO-d₆) δ ppm 8.68 (s, 1 H) 8.37 (d, J = 9.09 Hz, 1 H) 8.12(d, J = 3.79 Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.15 (d, J = 8.84 Hz, 1H) 6.74 (d, J = 3.54 Hz, 1 H) 6.03 (s, 1 H) 4.42 (d, J = 10.11 Hz, 4 H)1.96 (m, 1 H) 0.97-1.03 (m, 2 H) 0.77-0.80 (m, 2 H) 403.1 57-M

(DMSO-d₆) δ ppm 8.62 (s, 1 H) 8.45 (d, J = 8.84 Hz, 1 H) 8.11 (d, J =3.79 Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1 H) 7.11 (d, J = 8.84 Hz, 1 H) 6.66(d, J = 3.79 Hz, 1 H) 6.19 (s, 1 H) 4.26 (d, J = 1.77 Hz, 4H) 2.24-2.34(m, 4 H) 1.82-2.08 (m, 3 H) 417.2 57-N

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.30 (s, 1 H) 8.17 (d, J = 3.79 Hz, 1 H)7.47 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J = 8.84, 2.53 Hz, 1 H) 6.76 (d, J= 3.79 Hz, 1 H) 6.72 (s, 1 H) 4.07-4.13 (m, 4 H) 2.68 (d, J = 6.82 Hz, 2H) 2.01-2.03 (m, 1 H) 0.95 (d, J = 6.82 Hz, 6 H) 419.1 57-O

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.29 (d, J = 9.09 Hz, 1 H) 8.17 (d, J =3.79 Hz, 1 H) 7.47 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1H) 6.76 (d, J = 3.79 Hz, 1 H) 6.72 (s, 1 H) 4.06-4.30 (m, 4 H) 2.69 (s,2 H) 0.98 (s, 9 H) 433.1 57-P

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.30 (s, 1 H) 8.16 (d, J = 3.54 Hz, 1 H)7.47 (d, J = 2.53 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1 H) 6.76 (d, J= 3.79 Hz, 1 H) 6.67 (s, 1 H) 4.07-4.13 (m, 4 H) 2.83 (d, J = 3.54 Hz, 1H) 1.99 (br. S., 2 H) 1.76 (d, J = 16.17 Hz, 2 H) 1.34-1.51 (m, 6 H).445.0 57-Q

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.29 (d, J = 8.84 Hz, 1 H) 8.17 (d, J =3.79 Hz, 1H) 7.47 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1H) 6.76 (d, J = 3.79 Hz, 1 H) 6.69 (s, 1 H) 4.00-4.20 (m, 4 H) 3.11 (m,1 H) 1.29 (d, J = 7.07 Hz, 6 H). 405.1 57-R

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 8.17 (d, J =3.54 Hz, 1 H) 7.47 (d, J = 2.53 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1H) 6.72-6.82 (m, 2 H) 4.00- 4.20 (m, 4 H) 3.70 (m, 1 H) 2.32-2.43 (m, 2H) 2.17-2.31 (m, 2 H) 1.85-2.14 (m, 2 H). 417.1 57-S

(DMSO-d₆) δ ppm 8.55 (s, 1 H) 8.29 (d, J = 9.09 Hz, 1 H) 8.16 (d, J =3.79 Hz, 1 H) 7.46 (d, J = 2.27 Hz, 1 H) 7.14 (dd, J = 8.97, 2.40 Hz, 1H) 6.75 (d, J = 3.28 Hz, 1 H) 6.65 (s, 1 H) 4.04-4.16 (m, 4 H) 2.07-2.26(m, 1 H) 1.01-1.15 (m, 2 H) 0.87-0.98 (m, 2 H). 403.1 57-T

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.29 (d, J = 8.84 Hz, 1 H) 8.16 (d, J =3.79 Hz, 1 H) 7.47 (d, J = 2.53 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1H) 6.76 (d, J = 3.28 Hz, 1 H) 6.67 (s, 1 H) 4.01-4.19 (m, 4 H + 1 N—H)1.46 (s, 3 H) 1.07-1.21 (m, 2 H) 0.86-1.02 (m, 2 H). 417.1 57-U

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.29 (d, J = 8.84 Hz, 1 H) 8.17 (d, J =3.79 Hz, 1 H) 7.47 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1H) 6.73-6.78 (m, 2 H) 4.06- 4.13 (m, 4 H) 3.89-3.94 (m, 2 H) 3.43- 3.45(m, 1 H) 3.09-3.18 (m, 2 H) 1.90- 1.96 (m, 2 H) 1.64-1.75 (m, 2 H).447.1 57-V

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.29 (d, J = 9.09 Hz, 1 H) 8.17 (d, J =3.79 Hz, 1 H) 7.47 (d, J = 2.27 Hz, 1 H) 6.78 (s, 1 H) 6.76 (m, 2 H)4.08 (d, J = 2.02 Hz, 2 H) 4.07-4.14 (m, 2 H) 3.71-3.77 (m, 2 H)3.42-3.49 (m, 2 H) 2.06 (d, J = 5.56 Hz, 1 H) 2.06 (dd, J = 18.19, 3.54Hz, 1 H) 1.64-1.72 (m, 2 H) 1.35 (s, 3 H) 461.1 57-W

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.21 (d, J = 3.54 Hz, 1 H) 7.94 (d, J =3.79 Hz, 1 H) 7.95 (d, J = 8.08 Hz, 1 H) 7.56 (d, J = 5.56 Hz, 2 H) 7.55(s, 2 H) 7.45 (s, 2 H) 7.48 (d, J = 2.53 Hz, 1 H) 6.78 (s, 1 H) 4.08 (d,J = 1.77 Hz, 4 H) 439.1 57-X

(DMSO-d₆) δ ppm 8.55 (s, 1 H) 8.30 (s, 1 H) 8.20 (d, J = 3.54 Hz, 1 H)7.92 (m, 2 H) 7.52 (m, 2 H) 7.44 (d, J = 2.53 Hz, 2 H) 7.42 (s, 2 H)7.12 (m, 1 H) 6.73 (s, 1 H) 4.07 (m, 4 H). 457.1 57-Y

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.30 (s, 1 H) 8.17 (d, J = 3.79 Hz, 1 H)7.47 (d, J = 2.02 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1 H) 6.76 (d, J= 3.79 Hz, 1 H) 6.71 (s, 1 H) 4.09-4.13 (m, 4 H) 2.44 (s, 3 H). 337.157-Z

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.20 (d, J = 3.79 Hz, 1 H) 8.12 (d, J =9.09 Hz, 1 H) 7.31 (dd, J = 7.83 Hz, 9.09 Hz, 1 H) 6.89 (d, J = 3.79 Hz,1 H) 6.67 (s, 1 H) 4.23 (s, 2 H) 4.10-4.12 (m, 2 H) 1.34 (s, 9 H). 435.2(M − 1) 57-AA

(DMSO-d₆) δ ppm 8.62 (s, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 8.18 (d, J =3.8 Hz, 1 H), 7.49 (d, J = 2.3 Hz, 1 H), 7.17 (dd, J = 9.0, 2.4 Hz, 1H), 6.81 (s, 1 H), 6.78 (d, J = 3.8 Hz, 1 H), 4.31 (s, 2 H), 4.27 (s, 2H), 2.71-2.91 (m, 2 H), 1.46 (s, 6 H) 487.0 57-AB

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 8.16 (d, J =3.54 Hz, 1 H) 7.47 (d, J = 2.27 Hz, 1 H) 7.15-7.16 (m, 1 H) 7.16 (d, J =8.84 Hz, 1 H) 7.04 (s, 1 H) 6.76 (d, J = 3.28 Hz, 1 H) 4.06-4.18 (m, 2H) 4.11 (m, 2 H) 1.53-1.60 (m, 4 H) 471.1 57- AC

(DMSO-d₆) δ ppm 10.60 (d, J = 1.01 Hz, 1 H) 8.64 (s, 1 H) 8.29 (d, J =8.84 Hz, 1 H) 8.16 (d, J = 3.54 Hz, 1 H) 7.46 (d, J = 2.53 Hz, 1 H) 7.13(dd, J = 9.09, 2.53 Hz, 1 H) 6.72 (d, J = 3.54 Hz, 1 H) 6.16 (s, 1H)4.59 (br. S., 4 H) 3.79 (s, 3 H) 1.91 (s, 1 H) 0.87-1.06 (m, 2 H) 0.50-0.71 (m, 2 H) 416.1 57- AD

(DMSO-d₆) δ ppm 8.55 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 8.17 (d, J =3.79 Hz, 1 H) 7.46 (d, J = 2.27 Hz, 1 H) 7.14 (dd, J = 9.09, 2.53 Hz, 1H) 7.07 (s, 1 H) 6.75 (d, J = 3.79 Hz, 1 H) 4.03-4.16 (m, 4 H) 3.95 (s,3 H) 444.0

EXAMPLE 58 58-A.5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid4-nitro-phenyl ester

To a solution of 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole (943mg, 2.85 mmol) in THF (20 mL), sodium hydride (102 mg, 4.27 mmol, 60% inmineral oil) is added under nitrogen at 0° C., the resulting mixture isstirred for 1 h. Then this reaction mixture is added to the solution ofp-nitrophenyl chloromate in THF at 0° C. The mixture is stirred at 0° C.for 1 h. Then the mixture is quenched with water, the product isextracted with EtOAc (2×). Combined organic phases are washed water,brine, dried over sodium sulphate, filtered and condensed. The residueis separated by FCC (0-60% EtOAc/heptane) to provide the title compound.MS (ESI) m/z 496.9 (M+1).

58-B. 5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-trifluoromethyl-2H-pyrazol-3-yl)-amide

To a solution of 5-trifluoromethyl-2H-pyrazol-3-ylamine (876 mg, 5.80mmol) in THF (20 mL), NaH (348 mg, 8.70 mmol, 60% in mineral oil) isadded at 0° C. under nitrogen. The mixture is stirred at 0° C. for 1 h.At that point5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid4-nitro-phenyl ester (1440 mg, 2.90 mmol) in THF (10 mL) is added. Theresulting mixture is stirred overnight. Then the mixture is quenced withsat aq ammonium chloride. The product is extracted with EtOAc (2×). Thecombined organic layers are washed with water, brine, dried over sodiumsulfate, filtered, and condensed. The residue is separated by FCC (0-70%EtOAc/heptane) to provide the title compound. MS (ESI) m/z 509.0 (M+1).

58-C. 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-trifluoromethyl-1H-pyrazol-3-yl)-amide

A solution of5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-trifluoromethyl-2H-pyrazol-3-yl)-amide (150 mg, 0.295 mmol) and TFA(1.5 mL) is stirred at 110° C. for 1.5 h. After removal of the excessTFA, the residue is quenched with saturated aqueous sodium bicarbonatesolution. The mixture is then extracted with EtOAc (2×). The combinedorganic layers are washed with water, brine, dried over sodium sulphate,filtered, and condensed. The residue is separated by FCC (0-100%EtOAc/heptane) to provide the title compound. MS (ESI) m/z 418.9 (M+1).

58-D. 5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-trifluoromethyl-2H-pyrazol-3-yl)-amide

5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-trifluoromethyl-1H-pyrazol-3-yl)-amide (50 mg, 0.120 mmol) isdissolved in THF (5 mL) and TEA (0.033 ml, 0.239 mmol) is added at 0°C., followed by MsCl (0.014 ml, 0.179 mmol). The mixture is stirred at0° C. for 0.5 h. Then, the mixture is diluted with EtOAc and washed withwater, brine, dried over sodium sulphate, filtered, and condensed. Theresidue is then used directly as is in the next step.

To a solution of methanesulfonic acid6-[1-(5-trifluoromethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethylester (50 mg, 0.101 mmol), in THF (5 mL), methylamine in MeOH (0.5 mL,2.0 M) is added. The mixture is stirred at rt for 3 days and thencondensed. The residue is then separated by semi-prep HPLC to providethe title compound. MS (ESI) m/z 431.9 (M+1); ¹H NMR (400 MHz, MeOD) δppm 8.65 (s, 1H), 8.43 (d, J=9.09 Hz, 1H), 7.89 (d, J=3.79 Hz, 1H), 7.41(d, J=2.53 Hz, 1H), 7.11 (dd, J=8.97, 2.40 Hz, 1H), 7.00 (s, 1H), 6.74(d, J=3.54 Hz, 1H), 6.52 (s, 1H), 3.82 (s, 2H), 2.44 (s, 3H).

The following compounds are prepared with similar method.

58-E. 5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-tert-butyl-isoxazol-3-yl)-amide

MS (ESI) m/z 421.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.65 (s, 1H) 8.37(d, J=8.84 Hz, 1H) 7.91 (d, J=3.54 Hz, 1H) 7.41 (d, J=2.27 Hz, 1H) 7.12(dd, J=8.84, 2.27 Hz, 1H) 7.00 (s, 1H) 6.74 (d, J=3.79 Hz, 1H) 6.65 (s,1H) 3.79 (s, 2H) 2.41 (s, 3H) 1.39 (s, 9H).

58-F. 5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-tert-butyl-isoxazol-5-yl)-amide

MS (ESI) m/z 421.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.65 (s, 1H),8.42 (d, J=9.1 Hz, 1H), 7.93 (d, J=3.8 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H),7.05 (dd, J=8.8, 2.3 Hz, 1H), 6.94 (s, 1H), 6.64 (d, J=3.8 Hz, 1H), 6.30(s, 1H), 3.94 (s, 2H), 2.54 (s, 3H), 1.34 (s, 9H).

58-G.4-Fluoro-5-(6-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

MS (ESI) m/z 439.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.66 (d, J=1.01Hz, 1H), 8.19 (d, J=3.79 Hz, 1H), 8.15 (d, J=9.09 Hz, 1H), 7.28 (s, 1H),7.22 (d, J=1.01 Hz, 1H), 6.87 (d, J=3.79 Hz, 1H), 6.67 (s, 1H), 3.79 (s,2H), 3.31 (s, 3H), 1.34 (s, 9H).

58-H.4-Fluoro-5-(6-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 439.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.63 (d, J=1.01Hz, 1H), 8.13 (d, J=9.09 Hz, 1H), 7.90 (d, J=3.79 Hz, 1H), 7.17 (dd,J=8.84, 7.58 Hz, 1H), 7.13 (s, 1H), 6.80 (d, J=3.79 Hz, 1H), 6.38 (s,1H), 3.83 (s, 2H), 2.43 (s, 3H), 1.36 (s, 9H).

EXAMPLE 59 59-A.5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-tert-butyl-1H-pyrazol-3-yl)-amide

To a solution of5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid4-nitro-phenyl ester, Example 58A, (100 mg, 0.201 mmol) and5-tert-butyl-1H-pyrazol-3-ylamine (56.1 mg, 0.403 mmol) in THF (5 mL),diisopropylethylamine (0.11 mL, 0.604 mmol) is added. The resultingmixture is stirred at 65° C. overnight. After cooling to rt, the mixtureis quenced with water. The product is extracted with EtOAc (2×). Thecombined organic layers are washed with water, brine, dried over sodiumsulphate, filtered, and condensed. The residue is separated by FCC(0-60% EtOAc/heptane) to provide the title compound. MS (ESI) m/z 497.0(M+1)

59-B. 5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-tert-butyl-2H-pyrazol-3-yl)-amide

Elaboration of5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-tert-butyl-1H-pyrazol-3-yl)-amide into5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-tert-butyl-2H-pyrazol-3-yl)-amide is performed in similar fashion tothat described above for Example 58D. MS (ESI) m/z 420.0 (M+1); ¹H NMR(400 MHz, MeOD) δ ppm 8.65 (br. S., 1H), 8.35 (d, J=9.09 Hz, 1H), 7.90(d, J=3.28 Hz, 1H), 7.41 (br. S., 1H), 7.10 (d, J=8.84 Hz, 1H), 6.99(br. S., 1H), 6.72 (d, J=3.54 Hz, 1H), 6.37 (br. S., 1H), 3.78 (br. S.,2H), 2.41 (br. S., 3H), 1.36 (br. S., 9H).

The following compounds are prepared with similar method.

59-C.4-Fluoro-5-(6-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-trifluoromethyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 450.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.73 (s, 1H),8.32 (d, J=8.8 Hz, 1H), 8.09 (d, J=3.5 Hz, 1H), 7.23 (s, 1H), 7.20 (d,J=8.3 Hz, 1H), 6.77 (d, J=3.5 Hz, 1H), 6.54 (s, 1H), 4.02-4.14 (m, 1H),3.98 (s, 2H), 2.45 (s, 3H).

EXAMPLE 60 60-A. tert-Butyl4-(1-((4-nitrophenoxy)carbonyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of tert-butyl4-(1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate,Example 31-C, (1 g, 2.73 mmol) in 20 mL of THF, sodium hydride (0.164 g,4.09 mmol, 60% in mineral oil) is added at 0° C. After 1.5 h, a solutionof 4-nitrophenyl carbonochloridate (1.65 g, 8.19 mmol) in THF (10 mL) isadded. The mixture is allowed to warm to rt and stir overnight beforebeing quenched with ice water and extracted with EtOAc. The combinedorganic layers are washed with water and brine before being dried(Na₂SO₄) and concentrated. The residue is then separated by FCC (20-80%EtOAc/heptane) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm8.54 (s, 1H), 8.34-8.43 (m, 2H), 7.79 (d, J=3.8 Hz, 1H), 7.49-7.57 (m, 2H), 7.41 (d, J=2.3 Hz, 1H), 7.17 (dd, J=9.0, 2.4 Hz, 1H), 6.75 (d, J=3.5Hz, 1H), 5.31 (s, 1H), 4.65 (s, 2H), 3.80 (t, J=5.8 Hz, 2H), 2.95 (t,J=5.6 Hz, 2H), 1.53 (s, 9H).

60-B. tert-butyl4-(1-(3-((tert-butyldimethylsilyloxy)methyl)-5-trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of 2,2,6,6-tetramethylpiperidine (0.067 ml, 0.391 mmol) inTHF (1.5 mL), n-BuLi (0.13 mL, 0.331 mmol) is added at −78° C. After 15min,3-(tert-butyl-dimethyl-silanyloxymethyl)-5-trifluoromethyl-phenylamineis added. After an additional 15 min, a solution of tert-butyl4-(1-((4-nitrophenoxy)carbonyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylatein THF (3 mL) is added dropwise at −78° C. After 1 h the reaction isdiluted with EtOAc, quenched with ice water and extracted with EtOAc.The combined organic layers are washed with water, brine and dried(Na₂SO₄), and concentrated. The residue is separated by FCC (10-60%EtOAc/heptane) to give the title compound. MS (ESI) m/z 698.3 (M+1).

60-C.5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-hydroxymethyl-5-trifluoromethyl-phenyl)-amide

tert-Butyl4-(1-(3-((tert-butyldimethylsilyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-a]pyrimidine-7(8H)-carboxylateis treated with 50% TFA in DCM for 1 h. The solution is thenconcentrated and the residue is taken up into EtOAc, washed withsaturated sodium bicarbonate and brine before being dried (Na₂SO₄) andconcentrated. The residue is then separated by HPLC (C18; 12-42% I/H₂Owith 0.1% TFA) to give the title compound. MS (ESI) m/z 484.1 (M+1); ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.37 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=9.0Hz, 1H), 8.13 (d, J=3.7 Hz, 1H), 7.97 (d, J=10.9 Hz, 2H), 7.38-7.49 (m,2H), 7.12 (dd, J=9.0, 2.4 Hz, 1H), 6.79 (d, J=3.7 Hz, 1H), 5.50 (t,J=5.7 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.82 (s, 2H), 3.03 (t, J=5.7 Hz,2H), 2.72 (t, J=5.5 Hz, 2H).

The following compounds are prepared with similar method.

60-D.(±)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-hydroxymethyl-5-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 498.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.35 (s, 1H),8.40 (s, 1H), 8.27 (d, J=9.1 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.97 (d,J=11.1 Hz, 2H), 7.40-7.46 (m, 2H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.78(d, J=3.5 Hz, 1H), 5.48 (t, J=5.7 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H),3.79-3.96 (m, 2H), 2.90-3.03 (m, 1H), 2.85 (dd, J=17.1, 3.4 Hz, 1H),2.29-2.38 (m, 1H), 1.22 (d, J=6.3 Hz, 3H).

60-E.4-Fluoro-5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-trifluoromethyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 462.3 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.38 (br. S.,1H), 8.13-8.24 (m, 1H), 7.83-7.96 (m, 1H), 7.12-7.24 (m, 1H), 6.81-6.87(m, 1H), 6.54 (br. S., 1H), 3.97 (s, 2H), 3.14-3.24 (m, 2H), 2.92 (br.S., 2H).

60-F.(±)-4-Fluoro-5-(6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-trifluoromethyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 476.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (s, 1H),8.24 (d, J=8.84 Hz, 1H), 8.08 (d, J=3.79 Hz, 1H), 7.22 (t, J=8.08 Hz,1H), 6.80 (d, J=4.04 Hz, 1H), 6.57 (s, 1H), 3.90-3.96 (m, 2H), 3.07(ddd, J=10.11, 6.06, 4.04 Hz, 1H), 2.90-2.94 (m, 1H), 2.38-2.45 (m, 1H),1.24 (d, J=4.04 Hz, 3H).

EXAMPLE 61 61-A.(±)-5-Methyl-4-oxo-3,4,5,7-tetrahydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

To a suspension of NaH (9.72 g, 243 mmol, 60% in mineral oil) in toluene(100 mL), ethoxycarbonylamino-acetic acid ethyl ester (38 g, 187 mmol)is added at 0° C. The reaction is left stirring for 5 h at the sametemperature. At that point but-2-enoic acid ethyl ester (25.6 g, 224mmol) is added and the reaction allowed to warm up to rt and stirred forfurther 2 h. Ethanol (30 mL) is added and the reaction is thenevaporated. The crude 1-tert-butyl 3-ethyl2-methyl-4-oxopyrrolidine-1,3-dicarboxylate is dissolved in EtOH (1500mL), then formamidine acetate (343 g, 1189 mmol) is added followed bysodium ethoxide (47.2 g, 694 mmol). The reaction is left stirring at 90°C. for 8 h. The solvent is then removed and to the crude material asaturated solution of NH₄Cl (200 mL) is added followed by DCM (1 L). Thewater layer is extracted two times with DCM. The organics are dried andevaporate. The crude product is separated by FCC (DCM/MeOH 100:0 to90:10) to give the title compound. MS (ESI) m/z 252.2 (M+1).

61-B.(±)-4-(1H-Indol-5-yloxy)-5-methyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

To a solution of5-methyl-4-oxo-3,4,5,7-tetrahydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester (1 g, 3.98 mmol) in acetonitrile (40 ml), PyBOP(2.69 g, 5.17 mmol) is added, followed by DBU (1.200 ml, 7.96 mmol).After 20 min, 5-hydroxyindole (1.060 g, 7.96 mmol) is added. Thereaction is left stirring at rt overnight. The reaction mixture is thenevaporated, the crude product is added to a silica gel column and iseluted with heptane/ethyl acetate (100:0 to 60:40) to give the titlecompound. MS (ESI) m/z 367.05 (M+1).

61-C.(±)-5-Methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

To a solution of4-(1H-Indol-5-yloxy)-5-methyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester (400 mg, 1.092 mmol) in THF (10 mL) at 0° C.,sodium hydride (74.2 mg, 1.856 mmol, 60% in mineral oil) is added. After10 min, 1-isocyanato-3-trifluoromethyl-benzene (0.314 ml, 2.183 mmol) isadded and the reaction is allowed to reach rt. After 2 h, a saturatedsolution of NH₄Cl in water (5 mL) is added. The organics are extractedwith EtOAc (×3), dried and evaporated to give the crude5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-a]pyrimidine-6-carboxylicacid tert-butyl ester. MS (ESI) m/z 554.9 (M+1)

61-D.(±)-5-(5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester in DCM (20 mL), TFA (20 ml, 134 mmol) is added at0° C. After 30 min the reaction is warmed to rt. At this point, thereaction is evaporated and the crude product is dissolved in EtOAc. AFew drops of NH₄OH are added to freebase the amine and the whole mixtureis then evaporated. The crude product is added to a silica gel columnand is eluted with DCM/MeOH/NH₄OH (100:0:0 to 93:6:1) to give racemic545-Methyl-6,7-dihydro-5H-pyrrolo[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.9 (M+1); ¹H NMR(400 MHz, MeOD) δ ppm 8.50 (s, 1H) 8.33 (s, 1H) 8.06 (s, 1H) 7.94 (br.S., 2H) 7.57 (s, 1H) 7.42 (br. S., 2H) 7.12 (d, J=9.09 Hz, 1H) 6.75 (d,J=3.03 Hz, 1H) 4.70 (br. S., 1H) 4.10-4.22 (m, 2H) 1.60 (d, J=6.57 Hz, 3H). Racemate is then separated using chiral HPLC (IA column; 40%heptane, 60% Ethanol) to give the corresponding enantiomers D-1 and D-2.

61-D-1.(+)-5-(5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

R_(t)=6.09 min; MS (ESI) m/z 454.9 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm8.48 (s, 1H) 8.30 (d, J=9.09 Hz, 1H) 8.03 (s, 1H) 7.87 (d, J=3.54 Hz,2H) 7.52 (t, J=8.08 Hz, 1H) 7.38 (d, J=2.27 Hz, 2H) 7.07 (dd, J=8.84,2.27 Hz, 1H) 6.67 (d, J=3.79 Hz, 1H) 4.66 (q, J=6.57 Hz, 1H) 4.12-4.22(m, 2H) 1.56 (d, J=6.57 Hz, 3H).

61-D-2.(−)-5-(5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

R_(t)=7.71 min; MS (ESI) m/z 454.9 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm8.47 (d, J=1.77 Hz, 1H) 8.28 (dd, J=9.09, 1.77 Hz, 1H) 8.02 (s, 1H) 7.85(dd, J=3.66, 2.40 Hz, 2H) 7.49 (t, J=7.83 Hz, 1H) 7.36 (d, J=2.02 Hz,1H) 7.38 (d, J=8.59 Hz, 1H) 7.06 (dd, J=8.84, 2.27 Hz, 1H) 6.65 (d,J=2.53 Hz, 1H) 4.63 (d, J=6.06 Hz, 1H) 4.15-4.23 (m, 1H) 4.05-4.12 (m,1H) 1.55 (d, J=6.57 Hz, 3H)

The following compounds are prepared with similar method.

61-K(±)-5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (2-fluoro-5-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 472.9 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.49 (s, 1H) 8.29(d, J=8.84 Hz, 1H) 8.17 (d, J=6.82 Hz, 1H) 7.89 (d, J=3.79 Hz, 1H) 7.57(dd, J=8.72, 1.39 Hz, 1H) 7.29-7.45 (m, 2H) 7.10 (dd, J=8.84, 2.02 Hz,1H) 6.73 (d, J=3.79 Hz, 1H) 4.68 (q, J=6.48 Hz, 1H) 4.20 (d, J=1.77 Hz,1H) 4.06-4.15 (m, 1H) 1.58 (d, J=6.82 Hz, 3H).

EXAMPLE 62 62-A.(±)-5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-2H-pyrazol-3-yl)-amide

To a solution of tert-butyl4-(1H-indol-5-yloxy)-5-methyl-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate(150 mg, 0.409 mmol) in DMF (4 mL) at rt, di(1H-imidazol-1-yl)methanone(86 mg, 0.532 mmol) is added followed by TEA (0.34 mL, 2.46 mmol). After3 h at room temperature 5-tert-butyl-1H-pyrazol-3-amine (342 mg, 2.46mmol) is added and the reaction left stirring at rt for 48 h. At thispoint as 1N HCl solution in water (2 mL) is added and EtOAc (5 mL) isadded. The layers are separated and the water layer extracted 3 timeswith EtOAc. The organics are dried and evaporated. DCM (4 mL) and TFA(10 mL, 130 mmol) are added at 0° C. and the reaction allowed to warm tort over 1 h. At this point the reaction is complete. TFA/DCM isevaporated and then the product is taken up in EtOAc (100 mL). NH₄OH (20mL) is added and then water. The organics are separated and the waterlayer extracted with EtOAc (2 times). The organics are dried andevaporated. The crude product is added to a silica gel column (ISCO) andeluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to isolate5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-2H-pyrazol-3-yl)-amide. MS (ESI) m/z 432.0 (M+1); ¹HNMR (400 MHz, MeOD) δ ppm 8.50 (s, 1H) 8.33 (d, J=9.09 Hz, 1H) 7.89 (d,J=3.54 Hz, 1H) 7.41 (d, J=2.27 Hz, 1H) 7.10 (dd, J=8.97, 2.40 Hz, 1H)6.71 (d, J=3.54 Hz, 1H) 6.37 (s, 1H) 4.71 (d, J=6.57 Hz, 1H) 4.10-4.22(m, 2H) 1.60 (d, J=6.82 Hz, 3H) 1.37 (s, 9H).

The following compounds are prepared with similar method.

62-B.(±)-5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide

MS (ESI) m/z 444.9 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1H) 8.41(d, J=9.09 Hz, 1H) 7.88 (d, J=3.79 Hz, 1H) 7.43 (d, J=2.27 Hz, 1H) 7.14(dd, J=8.97, 2.40 Hz, 1H) 6.77 (d, J=3.79 Hz, 2H) 4.71 (d, J=6.32 Hz,1H) 4.22 (d, J=1.77 Hz, 1H) 4.16 (d, J=1.26 Hz, 1H) 1.60 (d, J=6.82 Hz,3H).

EXAMPLE 63 63-A.5-(6-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(140 mg, 0.320 mmol) is suspended in 1,2-dichloroethane (5 mL), andformaldehyde (50 μl, 0.672 mmol) and acetic acid (36 μl, 0.629 mmol) andsodium triacetoxyborohydride (139 mg, 0.656 mmol) are added and themixture heated to 60° C. overnight. The reaction is cooled to rt,diluted with water, brine and DCM. The organic phase is removed, dried,and concentrated to an oil that is purified via FCC (0-10% NH₃/MeOH:DCM)to obtain5-(6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.95 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.38 (s, 1H), 8.56 (s, 1H), 8.27 (d, J=9.09Hz, 1H), 8.09-8.13 (m, 2H), 7.96 (s, 1H), 7.65 (t, J=8.08 Hz, 1H),7.48-7.51 (m, 2H), 7.15 (dd, J=8.97, 2.40 Hz, 1H), 6.80 (d, J=3.79 Hz,1H), 3.91 (s, 4H), 2.52 (s, 3H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 63-B

(DMSO-d₆) δ ppm 10.38 (s, 1 H) 8.56 (s, 1 H) 8.27 (d, J = 9.09 Hz, 1 H)8.09-8.13 (m, 2 H) 7.96 (s, 1 H) 7.65 (s, 1 H) 7.48-7.52 (m, 2 H) 7.15(dd, J = 8.84, 2.27 Hz, 1 H) 6.80 (d, J = 3.79 Hz, 1 H) 3.92-3.96 (m, 4H) 2.75 (q, J = 7.33 Hz, 2 H) 1.07-1.14 (t, J = 7.07 Hz, 3 H 468.9 63-C

(DMSO-d₆) δ ppm 10.38 (s, 1 H) 8.56 (s, 1 H) 8.27 (d, J = 9.09 Hz, 1 H)8.09-8.13 (m, 2 H) 7.96-7.99 (m, 1 H) 7.62-7.67 (m, 1 H) 7.48- 7.52 (m,2 H) 7.15 (dd, J = 8.84, 2.53 Hz, 1 H) 6.80 (d, J = 3.79 Hz, 1 H) 3.98(d, J = 13.14 Hz, 4 H) 2.83 (s, 1 H) 1.07-1.14 (d, J = 6.32 Hz, 6 H)483.0 63-D

(DMSO-d₆) δ ppm 8.56 (s, 1 H) 8.27 (d, J = 9.09 Hz, 1 H) 8.09 (d, J =3.79 Hz, 1 H) 7.91 (s, 1H) 7.55-7.55 (m, 1H) 7.40-7.55 (m, 2 H) 7.14(dd, J = 8.97, 2.40 Hz, 1 H) 6.79 (d, J = 3.79 Hz, 1 H) 3.90 (s, 4 H)2.52 (s, 3 H) 472.0 63-E

(DMSO-d₆) δ ppm 11.28 (s, 1 H) 8.56 (s, 1 H) 8.30 (s, 1 H) 8.17 (d, J =3.79 Hz, 1 H) 7.47 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1H) 6.76 (d, J = 3.79 Hz, 1 H) 6.68 (s, 1 H) 3.90 (d, J = 1.52 Hz, 4 H)2.52 (s, 3 H) 1.34 (s, 9 H) 433.1 63-F

(DMSO-d₆) δ ppm 11.28 (br. S., 1 H) 8.56 (s, 1 H) 8.29 (d, J = 9.09 Hz,1 H) 8.17 (d, J = 3.54 Hz, 1 H) 7.47 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J =8.97, 2.40 Hz, 1 H) 6.77 (d, J = 3.79 Hz, 1 H) 6.68 (s, 1 H) 3.96-4.04(m, 4 H) 3.89 (dt, J = 11.56, 3.44 Hz, 2 H) 3.36 (td, J = 11.31, 1.89Hz, 2 H) 2.71 (s, 1 H) 1.85 (d, J = 1.26 Hz, 2 H) 1.48 (d, J = 4.04 Hz,2 H) 1.34 (s, 9 H) 503.1 63-G

(DMSO-d₆) δ ppm 8.52 (s, 1 H) 8.31 (d, J = 8.84 Hz, 1 H) 8.01 (m, 1 H)7.93 (d, J = 3.79 Hz, 1 H) 7.57 (s, 1 H) 7.34-7.50 (m, 2 H) 7.13 (dd, J= 8.97, 2.40 Hz, 1 H) 6.76 (d, J = 3.79 Hz, 1 H) 4.02 (d, J = 17.43 Hz,4 H) 3.84-3.96 (m, 1 H) 3.71-3.81 (m, 3 H) 3.64-3.71 (m, 2 H) 3.53- 3.64(m, 2 H) 3.33-3.53 (m, 1 H) 558.0 63-H

(DMSO-d₆) δ ppm 12.13 (s, 1 H) 10.57 (s, 1 H) 8.56 (s, 1 H) 8.30 (d, J =8.84 Hz, 1 H) 8.17 (br. S., 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.11 (dd, J= 8.84, 2.27 Hz, 1 H) 6.71 (d, J = 3.79 Hz, 1 H) 6.29 (br. S., 1 H) 3.92(d, J = 1.52 Hz, 4 H) 2.75 (q, J = 7.07 Hz, 2 H) 1.41 (s, 3 H) 1.11 (t,J = 7.20 Hz, 3 H) 0.86-1.03 (m, 2 H) 0.78 (m, 2 H) 444.1 63-I

(DMSO-d₆) δ ppm 12.13 (br. S., 1 H) 10.57 (s, 1 H) 8.55 (s, 1 H) 8.30(d, J = 8.84 Hz, 1 H) 8.17 (d, J = 3.28 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1H) 7.11 (dd, J = 8.84, 2.53 Hz, 1 H) 6.71 (d, J = 3.79 Hz, 1 H) 6.29 (s,1 H) 3.83-4.08 (m, 4 H) 2.68- 2.93 (m, 1 H) 1.41 (s, 3 H) 1.12 (d, J =6.32 Hz, 6 H) 0.88-0.97 (m, 2 H) 0.63-0.80 (m, 2 H) 458.1 63-J

(DMSO-d₆) δ ppm 12.13 (br. S., 1 H) 10.57 (br. S., 1 H) 8.56 (s, 1 H)8.30 (m, 1 H) 8.16 (m, 1 H) 7.44 (m, 1 H) 7.12 (m, 1 H) 6.70 (m, 1 H)6.29 (s, 1 H) 3.90 (s, 4 H) 2.55 (s, 3 H) 1.40 (s, 3 H) 0.92 (m, 2 H)0.78 (m, 2 H) 430.1

EXAMPLE 64 64-A.5-[6-(2-Hydroxy-ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(125.9 mg, 0.287 mmol) is dissolved in DMF (5 mL) and TEA (80 μL, 0.577mmol) is added followed by 2-bromoethanol (80 μL, 1.133 mmol). Thesolution is stirred at rt overnight. Then the reaction is concentratedand absorbed onto silica gel and separated via FCC (0-10%, 10% NH₄ inMeOH:DCM) to obtain5-(6-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.MS (ESI) m/z 484.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.38 (s, 1H)8.56 (s, 1H) 8.27 (d, J=9.09 Hz, 1H) 8.09-8.14 (m, 2H) 7.97 (d, J=7.58Hz, 1H) 7.65 (t, J=8.08 Hz, 1H) 7.48-7.52 (m, 2H) 7.15 (dd, J=8.84, 2.53Hz, 1H) 6.80 (d, J=3.54 Hz, 1H) 4.57 (t, J=5.56 Hz, 1H) 3.98-4.03 (m,4H) 3.58 (q, J=6.06 Hz, 2H) 2.82 (t, J=6.06 Hz, 2H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 64-B

(MeOD) δ ppm 10.27 (s, 1 H) 8.56 (s, 1 H) 8.24 (d, J = 8.84 Hz, 1 H)8.09 (d, J = 3.79 Hz, 1 H) 7.94 (s, 1 H) 7.70 (s, 1 H) 7.49 (d, J = 2.02Hz, 2 H) 7.15 (dd, J = 9.09, 2.27 Hz, 1 H) 6.81 (d, J = 3.79 Hz, 1 H)4.56 (t, J = 5.43 Hz, 1 H) 3.90-4.08 (m, 4 H) 3.58 (q, J = 5.89 Hz, 2 H)2.82 (t, J = 6.06 Hz, 2 H) 502.0 64-C

(DMSO-d₆) δ ppm 9.95 (s, 1 H) 8.36 (s, 1 H) 8.27 (d, J = 8.84 Hz, 1 H)8.03 (d, J = 3.79 Hz, 1 H) 7.36 (d, J = 2.53 Hz, 1 H) 7.07 (dd, J =8.97, 2.40 Hz, 1 H) 6.66 (d, J = 3.79 Hz, 1 H) 6.61 (s, 1 H) 3.95-3.98(m, 2 H) 3.90 (t, J = 2.27 Hz, 2 H) 3.60 (q, J = 5.56 Hz, 2 H) 3.42-3.46(m, 1 H) 2.82 (t, J = 5.81 Hz, 2 H) 1.21-1.27 (m, 9 H) 463.4 64-D

(DMSO-d₆) δ ppm 8.55 (s, 1 H) 8.46 (d, J = 8.59 Hz, 1 H) 8.11 (d, J =3.54 Hz, 1 H) 7.38 (d, J = 2.27 Hz, 1 H) 7.04 (dd, J = 9.09, 2.53 Hz, 1H) 6.63 (s, 1 H) 6.59 (br. S., 1 H) 3.96 (s, 4 H) 3.50 (t, J = 5.81 Hz,2 H) 3.26 (s, 3 H) 2.89 (t, J = 5.68 Hz, 2 H) 1.31-1.36 (m, 9 H) 477.164-E

(DMSO-d₆) δ ppm 10.57 (br. S., 1 H) 8.56 (s, 1 H) 8.28 (d, J = 8.59 Hz,1 H) 8.15 (s, 1 H) 7.44 (d, J = 2.27 Hz, 1 H) 7.11 (dd, J = 9.09, 2.53Hz, 1 H) 6.68 (s, 1 H) 6.29 (br. S., 1 H) 4.00 (s, 4 H) 3.58 (q, J =5.56 Hz, 2 H) 2.78- 2.80 (m, 2 H) 1.41 (s, 3 H) 0.93 (m, 2 H) 0.78 (m, 2H) 460.1

EXAMPLE 65 65-A.{4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-yl}-aceticacid

5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(121.9 mg, 0.277 mmol) is dissolved in DMF (5 mL) and TEA (200 μl, 1.435mmol) is added followed by t-butyl bromoacetate (101 μl, 0.693 mmol).The solution is stirred at rt overnight. The reaction is concentratedand then diluted with DCM (10 mL) and cooled to 0° C. TFA (5 mL) is thenadded and the ice bath is removed and the reaction is stirred at roomtemperature. The reaction is concentrated, basified with ammoniumhydroxide, and diluted with ethyl acetate. The solution is then treatedwith 1N HCl. The ethyl acetate is removed, dried and concentrated to aresidue. The residue is dissolved in DMSO and purified via HPLC (C18;20-100% I/H₂O with 0.1% TFA to obtain{4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-yl}-aceticacid. MS (ESI) m/z 498.9 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.50 (s,1H) 8.32 (d, J=8.84 Hz, 1H) 8.06 (s, 1H) 7.88-7.95 (m, 2H) 7.57 (t,J=7.96 Hz, 1H) 7.40-7.45 (m, 2H) 7.12 (dd, J=9.09, 2.02 Hz, 1H) 6.74 (d,J=3.79 Hz, 1H) 4.19 (d, J=9.35 Hz, 4H), 3.43 (s, 2H).

EXAMPLE 66 66-A.5-(6-Carbamoylmethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(217 mg, 0.494 mmol) is dissolved in DMF (5 mL) and TEA (160 μl, 1.15mmol) is added followed by 2-bromoacetamide (250 mg, 1.81 mmol). Thesolution is stirred at it for 1 h. The reaction is concentrated and theresidue absorbed onto silica gel and separated via FCC (0-10%, 10% NH₄in MeOH:DCM) to obtain5-(6-carbamoylmethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 497.9 (M+1); ¹H NMR(400 MHz, MeOD) δ ppm 10.38 (br. S., 1H) 8.58 (s, 1H) 8.27 (d, J=8.84Hz, 1H) 8.09-8.13 (m, 2H) 7.96 (s, 1H) 7.65 (t, J=8.08 Hz, 1H) 7.48-7.51(m, 2H) 7.38 (br. S., 1H) 7.09-7.17 (m, 2H) 6.80 (d, J=3.03 Hz, 1H) 4.12(dd, J=10.61, 2.02 Hz, 4H) 3.38 (s, 2H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 66-B

(DMSO-d₆) δ ppm 10.27 (s, 1 H) 8.58 (s, 1 H) 8.27 (s, 1 H) 8.09 (d, J =3.79 Hz, 1 H) 7.96 (s, 1 H) 7.66 (br. S., 1 H) 7.44-7.52 (m, 1 H) 7.14(dd, J = 8.84, 2.53 Hz, 3 H) 6.79 (d, J = 3.28 Hz, 1 H) 4.11 (dd, J =8.34, 2.02 Hz, 4 H) 3.34-3.43 (m, 2 H) 515.1 66-C

(DMSO-d₆) δ ppm 10.27 (s, 1 H) 8.58 (s, 1 H) 8.26 (s, 1 H) 8.09 (d, J =3.79 Hz, 1 H) 7.95 (s, 1 H) 7.67 (br. S., 1 H) 7.48 (overlap, m, 2 H)7.13 (dd, J = 9.09, 2.53 Hz, 1 H) 6.80 (d, J = 3.79 Hz, 1 H) 4.09 (dd, J= 7.45, 1.89 Hz, 4 H) 3.40 (s, 2 H) 2.63 (d, J = 4.55 Hz, 3 H) 529.066-D

(DMSO-d₆) δ ppm 11.28 (s, 1 H) 8.57 (s, 1 H) 8.30 (s, 1 H) 8.17 (d, J =3.79 Hz, 1 H) 7.47 (d, J = 2.53 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1H) 6.77 (d, J = 3.79 Hz, 1 H) 6.68 (s, 1 H) 4.09- 4.15 (m, 4 H) 3.38 (s,2 H) 1.34 (s, 9 H) 476.1 66-E

(DMSO-d₆) δ ppm 10.11 (s, 1 H) 8.54 (s, 1 H) 8.43 (d, J = 9.09 Hz, 1 H)8.19 (d, J = 3.79 Hz, 1 H) 7.44-7.51 (m, 1 H) 7.22 (dd, J = 8.97, 2.40Hz, 1 H) 6.81 (d, J = 3.79 Hz, 1 H) 6.76 (s, 1 H) 4.21 (t, J = 2.15 Hz,2 H) 4.14 (t, J = 2.27 Hz, 2 H) 3.48 (s, 2 H) 2.77-2.81 (m, 3 H) 1.42(s, 9 H) 490.4

EXAMPLE 67 67-A.4-[4-Fluoro-1-(4-fluoro-3-trifluoromethyl-phenylcarbamoyl)-2-methyl-1H-indol-5-yloxy]-pyridine-2-carboxylicacid methyl ester

A 1 M solution of LiHMDS in THF (4.33 mL, 4.33 mmol) is added to asolution of methyl 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)picolinate (1g, 3.33 mmol) in THF (50 mL) at −78° C. After 10 min,1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene (0.569 mL, 4.00 mmol)is added. After 40 min saturated aqueous NH₄Cl and EtOAc are added. Theaqueous layer is extracted further with EtOAc (200 mL). The combinedorganic phases are washed with brine (40 mL), dried over Na₂SO₄, andconcentrated in vacuo. The residue is purified via FCC (35%-90%EtOAc/heptane) to provide the title compound. MS (ESI) m/z 505.1 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.02 (s, 1H), 8.61 (d, J=5.56 Hz, 1H),8.13 (dd, J=6.32, 2.53 Hz, 1H), 7.96 (br. S., 1H), 7.60 (d, J=8.84 Hz,1H), 7.60 (t, J=9.73 Hz, 1H), 7.43 (d, J=2.53 Hz, 1H), 7.20-7.26 (m,2H), 6.67 (s, 1H), 3.84 (s, 3 H), 2.59 (s, 3H).

67-B.4-Fluoro-5-(2-hydroxymethyl-pyridin-4-yloxy)-2-methyl-indole-1-carboxylicacid (4-fluoro-3-trifluoromethyl-phenyl)-amide

4-[4-Fluoro-1-(4-fluoro-3-trifluoromethyl-phenylcarbamoyl)-2-methyl-1H-indol-5-yloxy]-pyridine-2-carboxylicacid methyl ester (450 mg, 0.890 mmol) is placed in THF (10 mL) andcooled to 0° C. A 1 M solution of DIBAL-H in hexanes (2.67 mL, 2.67mmol) is added. The reaction is stirred at 0° C. for 40 min. Thereaction is then allowed to warm to rt. After an additional 45 min, LCstill indicates the presence of intermediate aldehyde so an additional 1mL of 1 M DIBAL-H in hexanes is added. After 1 h further, 3 mL MeOH andNaBH₄ (0.14 g, 3.70 mmol) are added to force the reaction to completion.The reaction is stirred for 10 min and then diluted with EtOAc and H₂Oand stirred with 10 g sodium potassium tartrate for 1 h. The organiclayer is washed with brine, dried over Na₂SO₄, and concentrated invacuo. The residue is purified via FCC (50%-100% EtOAc/heptane) toprovide the title compound. MS (ESI) m/z 477.9 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.01 (s, 1H), 8.36 (d, J=5.56 Hz, 1H), 8.13 (dd, J=6.57,2.53 Hz, 1H), 7.94-7.98 (m, 1H), 7.56-7.62 (m, 2 H), 7.14-7.19 (m, 1H),6.89 (d, J=2.53 Hz, 1H), 6.85 (dd, J=5.56, 2.53 Hz, 1H), 6.65 (s, 1H),5.37 (t, J=5.68 Hz, 1H), 4.49 (d, J=5.81 Hz, 2H), 2.59 (s, 3H).

67-C. Methanesulfonic acid4-[4-fluoro-1-(4-fluoro-3-trifluoromethyl-phenylcarbamoyl)-2-methyl-1H-indol-5-yloxy]-pyridin-2-ylmethylester

4-Fluoro-5-(2-hydroxymethyl-pyridin-4-yloxy)-2-methyl-indole-1-carboxylicacid (4-fluoro-3-trifluoromethyl-phenyl)-amide (370 mg, 0.775 mmol) isplaced in dichloromethane (10 mL) and methanesulfonyl chloride (0.15 mL,1.92 mmol) and TEA (0.4 ml, 2.87 mmol) are added. The reaction isstirred at rt for 20 min before being diluted with dichloromethane andsaturated aqueous NH₄Cl. The aqueous layer is extracted further withdichloromethane. The combined organic layers are washed with brine anddried over Na₂SO₄, filtered, and concentrated to give the titlecompound. MS (ESI) m/z 555.8 (M+1)

67-D.5-(2-Cyclopropylaminomethyl-pyridin-4-yloxy)-4-fluoro-2-methyl-indole-1-carboxylicacid (4-fluoro-3-trifluoromethyl-phenyl)-amide

Methanesulfonic acid4-[4-fluoro-1-(4-fluoro-3-trifluoromethyl-phenylcarbamoyl)-2-methyl-1H-indol-5-yloxy]-pyridin-2-ylmethylester (80 mg, 0.144 mmol) is placed in THF (2 mL) and cyclopropylamine(0.030 mL, 0.432 mmol) is added and the reaction is stirred at 40° C.for 18 h. At that point DMF (0.2 mL) is added and the reactiontemperature is increased to 50° C. After an additional 4 h the reactionis judged complete by LCMS analysis. The reaction is diluted with EtOAcand H₂O. The aqueous layer is washed with EtOAc (3×50 mL). The organiclayers are then washed with brine and dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue is purified via FCC (0-7% MeOH with5% NH₃ in DCM) to provide the title compound. MS (ESI) m/z 516.9 (M+1);¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.34 (d, J=5.81 Hz, 1H), 8.06 (dd,J=6.06, 2.53 Hz, 1H), 7.85-7.98 (m, 1H), 7.53 (d, J=8.84 Hz, 1H), 7.38(t, J=9.60 Hz, 1H), 7.06 (t, J=8.21 Hz, 1H), 6.98 (d, J=2.27 Hz, 1H),6.81 (dd, J=5.81, 2.27 Hz, 1H), 6.53 (s, 1H), 3.85 (s, 2H), 2.61 (s, 3H), 2.11 (ddd, J=7.01, 3.35, 3.03 Hz, 1H), 0.34-0.49 (m, 4H).

EXAMPLE 68 68-A.5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-1H-indole

Triethylsilane (4 mL, 24.7 mmol) and TFA (6 mL) are added to5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole (0.22 g, 0.682 mmol)in 6 mL of acetonitrile and stirred at rt overnight. The reaction isconcentrated to an oil that is dissolved in EtOAc and washed with asaturated aqueous sodium bicarbonate. The organic layer is removed,dried, and concentrated to an to obtain crude5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-1H-indole. MS (ESI)m/z 334.2 (M+1).

68-B.5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-1H-indole (0.17 g,0.509 mmol) is dissolved in THF (3 mL) and cooled to 0° C. and1-isocyanato-3-trifluoromethyl-benzene (80 μL, 0.571 mmol) is added andthe reaction is warmed to rt overnight. The reaction is concentrated toan oil and absorbed onto silica gel and separated via FCC (0-50%EtOAc/heptane) to provide the title compound. MS (ESI) m/z 521.1 (M+1).

68-C. 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (4.11 g, 7.90 mmol) is dissolvedin TFA (100 mL) and is heated at 60° C. overnight. The reaction iscooled to rt and partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The organic layer is removed, dried, andconcentrated and the residue is absorbed onto silica gel and separatedvia FCC (0-100% ethyl acetate:heptane) to obtain the title compound. MS(ESI) m/z 431.1 (M+1).

68-D. Methanesulfonic acid6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidin-4-ylmethylester

5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (0.1001, 0.232 mmol) is dissolvedin THF (6 mL) and TEA (0.18 mL, 1.29 mmol) is added followed bymethanesulphonyl chloride (0.028 mL, 0.361 mmol). The solution isstirred for 15 min before being partitioned between ethyl acetate andsaturated aqueous sodium chloride. The layers are separated and theorganic layer is washed further with water. The organic layer is thenremoved, dried, and concentrated to obtain the title compound. MS (ESI)m/z 510.0 (m+1).

68-E.5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Methanesulfonic acid6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidin-4-ylmethylester (0.1331 g, 0.261 mmol) in 10 mL of THF is added to a solution of40% methylamine in water (0.4 mL, 4.58 mmol) and stirred at roomtemperature overnight. The reaction is diluted with ethyl acetate andwashed with water. The organic layer is removed, dried, and concentratedto an oil that is dissolved in ether, cooled to 0° C. and treated with0.3 mL 1 N HCl in ether to obtain5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide HCl salt. MS (ESI) m/z 444.1(m+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.26 (br. S., 1H) 8.93 (s, 1H)8.85 (s, 1H) 8.05 (s, 1H) 7.94 (d, J=8.84 Hz, 2H) 7.54 (t, J=8.08 Hz,1H) 7.36 (d, J=7.58 Hz, 1H) 7.21 (s, 1H) 7.11 (d, J=2.53 Hz, 1H) 6.98(dd, J=8.72, 2.40 Hz, 1H) 4.31 (br. S., 2H) 4.23 (t, J=8.59 Hz, 2H) 3.23(t, J=8.46 Hz, 2H) 2.64 (br. S., 3H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 68-F

(DMSO-d₆) δ ppm 8.93 (s, 1 H) 8.85 (s, 1 H) 8.05 (s, 1 H) 7.88-7.96 (m,2 H) 7.54 (t, J = 8.08 Hz, 1 H) 7.31-7.38 (m, 2 H) 7.11 (d, J = 1.77 Hz,1 H) 6.99 (dd, J = 8.72, 2.15 Hz, 1 H) 4.47 (br. S., 2 H) 4.23 (t, J =8.59 Hz, 2 H) 3.86 (br. S., 3 H) 3.78 (d, J = 5.05 Hz, 1 H) 3.31-3.40(m, 2 H) 3.24 (m, 4 H) 500.0 68-G

(DMSO-d₆) δ ppm 8.93 (s, 1 H) 8.82 (s, 1 H) 8.15 (br. S., 2 H) 8.05 (s,1 H) 7.88-7.95 (m, 2 H) 7.54 (t, J = 7.96 Hz, 1 H) 7.36 (d, J = 8.08 Hz,1 H) 7.18 (s, 1 H) 7.10 (d, J = 2.53 Hz, 1 H) 6.97 (dd, J = 8.59, 2.53Hz, 1 H) 4.15- 4.26 (m, 4 H) 3.23 (t, J = 8.59 Hz, 2 H). 430.0 68-H

(DMSO-d₆) δ ppm 9.45 (br. S., 1 H) 8.93 (s, 1 H) 8.86 (d, J = 1.01 Hz, 1H) 8.05 (s, 1 H) 7.88-8.00 (m, 2 H) 7.54 (t, J = 7.83 Hz, 1 H) 7.36 (d,J = 7.83 Hz, 1 H) 7.25 (s, 1 H) 7.11 (d, J = 2.53 Hz, 1 H) 6.98 (dd, J =8.59, 2.53 Hz, 1 H) 4.34-4.39 (m, 2 H) 3.93 (d, J = 11.37 Hz, 2 H)3.19-3.32 (m, 4 H) 1.99 (d, J = 1.52 Hz, 2 H) 1.67 (dd, J = 12.13, 4.55Hz, 2 H) 1.04 (d, J = 6.06 Hz, 3 H). 514.1 68-I

(DMSO-d₆) δ ppm 10.71 (br. S., 1 H) 9.00 (br. S., 1 H) 8.85 (s, 1 H)8.07 (br. S., 1 H) 7.93 (t, J = 7.45 Hz, 1 H) 7.48- 7.58 (m, 1 H) 7.43(br. S., 1 H) 7.35 (d, J = 6.57 Hz, 1 H) 7.11 (br. S., 1 H) 6.99 (d, J =8.08 Hz, 1 H) 4.41 (br. S., 2 H) 4.20-4.30 (m, 2 H) 3.29-3.48 (m, 3 H)3.23 (br. S., 2 H) 3.00 (br. S., 2 H) 1.80 (br. S., 4 H) 1.36 (br. S., 1H) 498.0 68-J

(DMSO-d₆) δ ppm 10.35 (br. S., 1 H) 8.94 (s, 1 H) 8.87 (d, J = 1.01 Hz,1 H) 8.05 (s, 1 H) 7.88-7.96 (m, 2 H) 7.54 (t, J = 8.08 Hz, 1 H)7.32-7.37 (m, 1 H) 7.12 (d, J = 2.27 Hz, 1 H) 6.99 (dd, J = 8.72, 2.65Hz, 1 H) 4.42 (br. S., 4 H) 4.23 (t, J = 8.72 Hz, 2 H) 3.23 (t, J = 8.59Hz, 2 H) 2.78 (s, 3 H) 1.27 (t, J = 7.20 Hz, 3 H) 472.0 68-K

(DMSO-d₆) δ ppm 8.90 (d, J = 19.71 Hz, 2 H) 8.05 (s, 1 H) 7.88-7.96 (m,2 H) 7.54 (t, J = 7.83 Hz, 1 H) 7.32- 7.37 (m, 2 H) 7.12 (d, J = 2.53Hz, 1 H) 6.99 (dd, J = 8.84, 2.53 Hz, 1 H) 4.47 (d, J = 3.79 Hz, 2 H)4.23 (t, J = 8.59 Hz, 2 H) 3.14-3.26 (m, 6 H) 1.15-1.28 (m, 6 H). 486.168-L

(DMSO-d₆) δ ppm 9.08 (br. S., 1 H) 8.94 (s, 1 H) 8.85 (s, 1 H) 8.05 (s,1 H) 7.84-8.00 (m, 2 H) 7.54 (t, J = 7.96 Hz, 1 H) 7.29-7.42 (m, 1 H)7.11 (d, J = 2.53 Hz, 1 H) 6.99 (dd, J = 8.59, 2.53 Hz, 1 H) 4.48 (br.S., 2 H) 4.23 (t, J = 8.59 Hz, 2 H) 3.53 (br. S., 4 H) 3.17- 3.29 (m, 3H) 2.99 (br. S., 2 H) 2.81-2.90 (m, 1 H) 516.2 68-M

(DMSO-d₆) δ ppm 9.23 (br. S, 1 H) 8.94 (s, 1 H) 8.86 (d, J = 1.01 Hz, 1H) 8.05 (s, 1 H) 7.88-7.96 (m, 2 H) 7.54 (t, J = 7.96 Hz, 1 H) 7.36 (d,J = 7.83 Hz, 1 H) 7.26 (s, 1 H) 7.11 (d, J = 2.53 Hz, 1 H) 6.98 (dd, J =8.84, 2.53 Hz, 1 H) 4.32 (s, 2 H) 4.23 (t, J = 8.59 Hz, 2 H) 3.40-3.50(m, 1 H) 3.23 (t, J = 8.59 Hz, 2 H) 1.29 (d, J = 6.57 Hz, 6 H) 472.068-N

(DMSO-d₆) δ ppm 9.34 (br. S., 2 H) 8.93 (s, 1 H) 8.86 (d, J = 1.01 Hz, 1H) 8.05 (s, 1 H) 7.88-7.96 (m, 1 H) 7.54 (t, J = 7.96 Hz, 1 H) 7.36 (d,J = 7.83 Hz, 1 H) 7.25 (d, J = 1.01 Hz, 1 H) 7.11 (d, J = 2.53 Hz, 1 H)6.98 (dd, J = 8.59, 2.53 Hz, 1 H) 4.32 (t, J = 5.94 Hz, 2 H) 4.23 (t, J= 8.59 Hz, 2 H) 3.40-3.50 (m, 1 H) 3.23 (t, J = 8.72 Hz, 2 H) 1.97 (br.S., 2 H) 1.64-1.76 (m, 4 H) 1.49-1.58 (m, 2 H) 498.0 68-O

(DMSO-d₆) δ ppm 10.50 (br. S., 1 H) 8.94 (s, 1 H) 8.86 (d, J = 1.01 Hz,1 H) 8.05 (s, 1 H) 7.88-7.96 (m, 1 H) 7.54 (t, J = 7.96 Hz, 1 H) 7.36(d, J = 7.83 Hz, 1 H) 7.30 (d, J = 1.01 Hz, 1 H) 7.12 (d, J = 2.53 Hz, 1H) 6.99 (dd, J = 8.72, 2.65 Hz, 1 H) 4.46 (s, 2 H) 4.23 (t, J = 8.72 Hz,2 H) 3.23 (t, J = 8.46 Hz, 2 H) 2.83 (s, 6 H). 458.0

EXAMPLE 69 69-A. 5-(2-Methyl-pyridin-4-yloxy)-1H-indole

5-Hydroxy indole (133 mg, 3.76 mmol), 4-bromo-2-methylpyridine (711 mg,4.13 mmol) and cesium carbonate (2.45 g, 7.52 mmol) are stirred in DMSO(3 mL) at 110° C. for 12 h. The mixture is then partitioned between DCMand water. Organic layer is removed, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue is purified via FCC (EtOAc/heptanes2:8 to EtOAc) to provide the title compound. MS (ESI) m/z 225.1 (M+1);¹H NMR (400 MHz, MeOD) δ ppm 8.20 (d, J=5.8 Hz, 1H), 7.46 (d, J=8.6 Hz,1H), 7.33 (d, J=3.0 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 6.86 (dd, J=8.8,2.3 Hz, 1H), 6.67-6.77 (m, 2H), 6.48 (d, J=3.0 Hz, 1H), 2.43 (s, 3H).

69-B. 5-(2-Methyl-pyridin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethylphenyl)-amide

To a solution of 2,2,6,6-Tetramethylpiperidine (0.27 mL, 1.08 mmol) inTHF (5 mL) at −78° C. is added nBuLi (0.69 mL, 1.72 mmol, 2.5M inhexanes). The solution is allowed to stir for 15 min before a THFsolution (2 mL) of 5-(2-methyl-pyridin-4-yloxy)-1H-indole (242 mg, 1.08mmol) is added. This solution is then stirred for 30 min before additionof 3-trifluoromethylphenyl isocyanate (0.30 mL, 2.16 mmol) is added. Thereaction is allowed to stir at room temperature for 3 h before beingpartitioned between EtOAc and pH 7 buffer solution. The organic layer isdried over anhydrous Na₂SO₄, and concentrated. The residue is purifiedvia FCC (10-70% EtOAc/heptane) to give the title compound. MS (ESI) m/z412.3 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.38 (d, J=8.8 Hz, 1H), 8.24(d, J=5.8 Hz, 1H), 8.08 (s, 1H), 7.97 (d, J=3.8 Hz, 1H), 7.91 (d, J=8.1Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.46 (d, J=7.1 Hz, 1H), 7.38 (d, J=2.3Hz, 1H), 7.09 (dd, J=8.8, 2.3 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.72-6.78(m, 2H), 2.45 (s, 3H).

EXAMPLE 70 70-A.5-(benzyloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a solution of 2,2,6,6-tetramethylpiperidine (8.38 mL, 49.3 mmol) in200 mL of THF at −78° C., 2.5 M n-butyl lithium (18 mL, 44.8 mmol) isadded. After 15 min, 5-(benzyloxy)-1H-indole is added. After the other15 min, 1-isocyanato-3-(trifluoromethyl)benzene is added dropwise at−78° C. and then stirred for 2 h at rt. The reaction is concentrated andthe resulting solid is triturated with heptane and collected byfiltration to give the title compound. MS (ESI) m/z 411.1 (M+1).

70-B. 70-B-15-hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and70-B-2 5-hydroxy-N-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide

A mixture of5-(benzyloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (6g, 14.6 mmol) in 60 mL of EtOH and 30 mL of EtOAc with Pd/C (0.6 g) isstirred under a hydrogen atmosphere (1 atm) at rt for 3.5 h. AdditionalPd/C (0.6 g) is added and the mixture allowed to stir overnight. Afterfiltration and concentration the solid was triturated with DCM andheptane to give a mixture of5-hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and5-hydroxy-N-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (6:4)which is carried on to next step.

70-C.5-(2-chloropyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

A mixture of5-hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and5-hydroxy-N-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (6:4) (3g) is mixed with sodium hydroxide (0.45 g, 11.2 mmol) and2,4-dichloropyrimidine (1.68 g, 11.2 mmol) in 50 mL of acetone and 50 mLof water at 0° C. and stirred for 1.5 h. Additional sodium hydroxide(0.075 g, 1.88 mmol) and (0.279 g, 1.88 mmol) are added. Afteradditional 30 min stirring the reaction is concentrated, diluted withEtOAc, washed with water and brine before the organic layer is driedover sodium sulfate and concentrated. The residue is separated via FCC(5-50% EtOAc in heptane) to give5-(2-chloropyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.¹H NMR (400 MHz, CDCl₃) δ ppm 8.45 (d, J=5.7 Hz, 1H), 8.24 (d, J=9.0 Hz,1H), 7.86 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.60 (d, J=3.7 Hz, 1H), 7.55(t, J=8.0 Hz, 1H), 7.45-7.50 (m, 2H), 7.42 (d, J=2.1 Hz, 1H), 7.15 (dd,J=8.9, 2.3 Hz, 1H), 6.82 (d, J=5.7 Hz, 1H), 6.73 (dd, J=3.7, 0.6 Hz,1H).

70-D.5-(2-cyanopyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a solution of5-(2-chloropyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(1.76 g, 4.074 mmol) in 80 mL of a mixture of DMSO and H₂O (85:15),DABCO (0.92 g, 8.148 mmol) is added followed by KCN (0.53 g, 8.148mmol). The mixture is stirred at rt for 2.5 h before being diluted withEtOAc, washed with H₂O and brine. The organic layer is dried overNa₂SO₄, filtered, and concentrated. The residue is purified by FCC(0-50% EtOAc/heptane) to give the title compound. MS (ESI) m/z 424.0(M+1)

70-E.5-(2-(aminomethyl)pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a solution of5-(2-cyanopyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(1.49 g, 3.52 mmol) in 70 mL of THF at −78° C., DIBAL (1 M in DCM, 10.6mL) is added dropwise and stirred for 45 min at −78° C. The reaction isquenched with Roechelle's salt solution and extracted with DCM (×3). Thecombined organic layers are washed with brine and dried over Na₂SO₄.After concentration, the residue is purified by HPLC (5-90% I in H₂Owith 0.1% TFA to give the title compound. MS (ESI) m/z 428.1 (M+1); ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.41 (s, 1H), 8.73 (d, J=5.8 Hz, 1H),8.23-8.37 (m, 3H), 8.17 (d, J=3.8 Hz, 1H), 8.10 (s, 1H), 7.97 (d, J=8.3Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.48-7.56 (m, 2H), 7.18 (dd, J=8.8, 2.5Hz, 1H), 7.02 (d, J=5.8 Hz, 1H), 6.82 (d, J=3.8 Hz, 1H), 4.12-4.20 (m,2H)

EXAMPLE 71 71-A. 5-(Pyridin-4-ylmethoxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl) Amide

5-Hydroxy-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide,Example 70-B-1, (150 mg, 0.47 mmol), pyridine-4-yl-methanol (51 mg, 0.47mmol) and cyanomethylenetri-n-butylphosphorane (0.17 mL, 0.70 mmol) areheated in a sealed tube at 100° C. for 15 h. The reaction is thenconcentrated in vacuo and separated directly via FCC (10-90EtOAc/heptane) to give the title compound. MS (ESI) m/z 412.3 (M+1), ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.26 (s, 1H), 8.58 (d, J=6.1 Hz, 2H), 8.16(d, J=9.1 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J=3.8 Hz, 1H), 7.95 (d, J=8.8Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.43-7.51 (m, 3H), 7.23 (d, J=2.3 Hz,1H), 7.05 (dd, J=9.1, 2.5 Hz, 1H), 6.71 (d, J=3.3 Hz, 1H), 5.24 (s, 2H).

EXAMPLE 72 72-A. (2-Isopropylamino-pyridin-4-yl)-methanol

A mixture of (2-bromo-pyridin-4-yl)-methanol (500 mg, 2.66 mmol),isopropylamine (0.45 mL, 5.32 mmol), NatOBu (790 mg, 7.98 mmol) andPd(tBu₃P)₂ (136 mg, 0.26 mmol) in 1,4-dioxane (5 mL) is heated in amicrowave reactor at 110° C. for 45 min. The reaction is diluted withDCM (50 mL) and washed with saturated aqueous NH₄Cl. The organic layeris removed, dried over anhydrous Na₂SO₄, and concentrated in vacuo togive the title compound that is used without further purification. MS(ESI) m/z 167.1 (M+1).

72-B. 5-(2-Isopropylamino-pyridin-4-ylmethoxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

5-Hydroxy-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (100mg, 0.31 mmol), (2-isopropylamino-pyridin-4-yl)-methanol (63 mg, 0.37mmol) and cyanomethylenetri-n-butylphosphorane (112 mg, 0.46 mmol) areheated in a sealed tube at 90° C. for 2 h. The solution is thenconcentrated in vacuo and the residue separated via semi-prep HPLC (C18;10-100% I/H₂O with 0.1% TFA) to give the title compound. MS (ESI) m/z469.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.26 (s, 1H), 8.14 (d,J=9.1 Hz, 1H), 8.07 (s, 1H), 8.02 (d, J=3.5 Hz, 1H), 7.90-7.98 (m, 2 H),7.63 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H),7.00 (dd, J=9.0, 2.7 Hz, 1H), 6.70 (d, J=3.8 Hz, 1H), 6.45-6.52 (m, 2H),6.35 (d, J=7.6 Hz, 1H), 5.03 (s, 2H), 3.90-4.03 (m, 1H), 1.12 (d, J=6.6Hz, 6H).

EXAMPLE 73 73-A. 5-(2-chloropyrimidin-4-yloxy)-1H-indole

To a solution of 1H-indol-5-ol (5.0 g, 37.6 mmol) in 40 mL of1,2,4-dichloropyrimidine (5.6 g, 37.6 mmol) is added and the solution iscooled to 0° C. and DBU (5.71 mL, 37.6 mmol) is added dropwise. Thereaction is allowed to warm to rt and stir for 2 h before beingconcentrated. The residue is taken up in EtOAc, washed with H₂O (×2),brine and the organic layer is dried over Na₂SO₄. After concentration,the resulting solid is triturated with DCM and heptane and collected byfiltration to give the title compound. ¹H NMR (400 MHz, CD₂Cl₂) δ ppm8.29-8.50 (m, 2H), 7.35-7.49 (m, 2H), 7.29 (t, J=2.9 Hz, 1H), 6.97 (dd,J=8.6, 2.3 Hz, 1H), 6.70 (d, J=5.8 Hz, 1H), 6.53-6.60 (m, 1H).

73-B. 5-(2-vinylpyrimidin-4-yloxy)-1H-indole

A mixture of 5-(2-chloropyrimidin-4-yloxy)-1H-indole (1 g, 4.082 mmol),tri-butyl(vinyl)stannane (1.79 mL, 6.12 mmol) and Pd(PPh₃)₄ (0.377 g,0.327 mmol) in 1,4-dioxane (10 mL) and toluene (10 mL) is heated in amicrowave reactor at 140° C. for 30 min. The reaction is then dilutedwith EtOAc, washed with H₂O (×3), brine and the organic layer is driedover Na₂SO₄. After concentration, the residue is purified by FCC (0-50%EtOAc/heptane) to give the title compound. MS (ESI) m/z 238.0 (M+1).

73-C. 4-(2-(4-(1H-indol-5-yloxy)pyrimidin-2-yl)ethyl)morpholine

A mixture of 5-(2-vinylpyrimidin-4-yloxy)-1H-indole (0.45 g, 1.90 mmol),morpholine (0.33 mL, 3.80 mmol) and acetic acid (0.20 mL, 3.42 mmol) in15 mL of EtOH is heated in a microwave reactor at 120° C. for 30 min. Atthat point the solution is concentrated and the residue is taken up inEtOAc, washed with H₂O (×2), sat aq NaHCO₃, brine and the organic layeris dried over Na₂SO₄. After concentration the title compound is obtainedand carried on to next step without further purification. MS (ESI) m/z325.1 (M+1).

73-D.5-(2-(2-morpholinoethyl)pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a mixture of 2,2,6,6-tetramethylpiperidine (TMP, 0.18 mL, 1.05 mmol)and THF (12 mL) at −78° C., n-BuLi (0.42 mL, 1 M in hexane) is added.After 10 min, a solution of(4-(2-(4-(1H-indol-5-yloxy)pyrimidin-2-yl)ethyl)morpholine in 5 mL ofTHF is added dropwise. The solution is stirred at −78° C. for 30 min andthen 1-isocyanato-3-(trifluoromethyl)benzene is added dropwise andstirring continued at −78° C. for an additional 1 h. The reaction isquenched with MeOH and then concentrated. The residue is taken up inEtOAc, washed with H₂O (×2), brine and the organic layer is dried overNa₂SO₄. After concentration, the residue is purified by FCC (0-5%MeOH/DCM) and then by semi-prep HPLC (20-60% CH₃CN in H₂O with 0.1%NH₄OH to give title compound. MS (ESI) m/z 512.2 (M+1); ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.38 (br. S., 1H), 8.56 (d, J=5.8 Hz, 1H), 8.29 (d,J=9.1 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 8.09 (s, 1H), 7.97 (d, J=9.1 Hz,1H), 7.64 (t, J=8.0 Hz, 1H), 7.44-7.53 (m, 2H), 7.14 (dd, J=9.0, 2.4 Hz,1H), 6.85 (d, J=5.8 Hz, 1H), 6.78-6.82 (m, 1H), 3.46-3.52 (m, 4H), 2.85(t, J=7.3 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.27-2.37 (m, 4H)

The following compounds are prepared with similar method.

73-E.5-(2-(2-(isopropylamino)ethyl)pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

MS (ESI) m/z 484.3 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (d, J=5.8Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 8.09 (s, 1H),7.97 (d, J=8.6 Hz, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.45-7.53 (m, 2H), 7.15(dd, J=8.8, 2.3 Hz, 1H), 6.87 (d, J=5.8 Hz, 1H), 6.79 (d, J=3.5 Hz, 1H),2.80 (s, 4H), 2.55-2.68 (m, 1H), 0.85 (d, J=6.1 Hz, 6H)

EXAMPLE 74 74-A.5-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-pyridin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of acid4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylicacid, Example 28-A, (0.100 g, 0.226 mmol) in DCM (5 mL) is added Et₃N(0.09 mL), DMF (2 drops) and oxalyl chloride (0.17 mL, 0.340 mmol, 2.0 MDCM). After 0.5 h tert-butyl carbazate is added (0.045 g, 0.340 mmol).After 1.5 h the solution is diluted with DCM (10 mL) and then washedwith pH 7 buffer (15 mL). The organic layer is then dried (Na₂SO₄),filtered, and concentrated. The residue is separated via FCC (30-60%EtOAc/heptane) to giveN′-{4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carbonyl}-hydrazinecarboxylicacid tert-butyl ester. MS (ESI) m/z 484.3 (M+1).

TheN′-{4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carbonyl}-hydrazinecarboxylicacid tert-butyl ester (0.105 g, 0.189 mmol) is then taken up in DCM (2mL) and treated with TFA (0.5 mL). After 2 h the solution inconcentrated in vacuo. The resulting residue is then taken up in THF (3mL) and Et₃N (0.079 mL) and carbonyl diimidazole is added (0.046 g,0.283 mmol). After 0.5 h the solution is concentrated and the residue isseparated via semi-prep HPLC (20-100% I/H₂O with 0.1% NH₄OH) to give thetitle compound. MS (ESI) m/z 484.3 (M+1).

EXAMPLE 75 75-A.1-{6-[1-(4-Fluoro-3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-piperidine-3-carboxylicacid

To a solution of1-{6-[1-(4-fluoro-3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-piperidine-3-carboxylicacid ethyl ester (prepared by similar method to Example 19) (0.32 g,0.55 mmol), in THF (5.5 mL), LiOH (0.92 g, 22 mmol) in H₂O (8.75 mL) isadded and the reaction allowed to stir overnight. The reaction isacidified to pH 4 with 1 N HCl and then extracted with EtOAc (3×). Thecompound is then purified by semi-prep HPLC (12-48% CH₃CN/H₂O with 0.1%TFA) to give the title compound. MS (ESI) m/z 558.9 (M+1).

EXAMPLE 76 76-A.5-(6-(benzyloxymethyl)pyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a solution of TMP (1.15 ml, 6.757 mmol) in 30 ml of THF at −78° C.,n-BuLi (1.15 mL, 2.88 mmol) is added. After 10 min, a solution of5-(6-(benzyloxymethyl)pyrimidin-4-yloxy)-1H-indole (0.868 g, 2.62 mmol)in 5 mL of THF is added dropwise and stirred at −78° C. Reaction 2: To asolution of 3-methoxy-5-(trifluoromethyl)aniline (0.6 g, 3.14 mmol) in20 mL of DCE at 0° C., triphosgene (0.931 g, 3.14 mmol) is addedfollowed by TEA (1.74 mL, 12.6 mmol). The solution is a allowed to warmto rt and stir for 45 min. At that point reaction 2 is added to reaction1 dropwise at −78° C. and stirred for 2 h. The reaction is then quenchedwith MeOH and concentrated. The residue is taken up in EtOAc, washedwith H₂O (×2), brine and the organic layer is dried over Na₂SO₄. Afterconcentration, the residue is purified by FCC (5-65% EtOAc/haptane) togive the title compound which is carried on to the next step as is. MS(ESI) m/z 549.1 (M+1).

76-B.5-(6-(hydroxymethyl)pyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

5-(6-(Benzyloxymethyl)pyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(0.94 g, 1.72 mmol) is treated with TFA (9.5 mL) at 60° C. for 24 h.After concentration, the residue is taken up in EtOAc, washed withsaturated NaHCO₃ (×2), brine and the organic layer is dried over Na₂SO₄.After concentration, the residue is purified by FCC (20-90%EtOAc/heptane) and then semi-prep HPLC (20-60% CH₃CN in H₂O with 0.1%NH₄OH) to give the title compound. MS (ESI) m/z 459.0 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.35 (br. S., 1H), 8.65 (s, 1H), 8.31 (d, J=9.1 Hz,1H), 8.12 (d, J=3.5 Hz, 1H), 7.69 (s, 1H), 7.60 (t, J=1.9 Hz, 1H), 7.50(d, J=2.3 Hz, 1H), 7.15 (dd, J=8.8, 2.3 Hz, 1H), 6.95-7.06 (m, 2H), 6.80(d, J=3.5 Hz, 1H), 5.61 (t, J=5.7 Hz, 1H), 4.52 (d, J=5.8 Hz, 2H), 3.86(s, 3H).

76-C.5-(6-formylpyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a solution of5-(6-(hydroxymethyl)pyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(0.260 g, 0.568 mmol) in DCM (8 mL) is added DMP (0.265 g, 0.624 mmol)at 0° C. The mixture is then allowed to warm to it and stir for 2 hbefore being diluted with EtOAc and washed with aqueous NaHCO₃/Na₂S₂O₄.The organic layer is then dried and concentrated and the residueseparated via FCC (10-60% EtOAc/heptane) to give the title compound. MS(ESI) m/z 457.0 (M+1).

76-D.N-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(6-((methylamino)methyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide

To a solution of5-(6-formylpyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide(0.219 g, 0.479 mmol) in 3 mL of DCM, 2 M methylamine in THF (0.72 mL,1.43 mmol) is added and stirred at it for 45 min. At that pointNa(Oac)₃BH (0.406 g, 1.92 mmol) is added followed by acetic acid (0.14mL) and the mixture is stirred at rt for 1.5 h before being diluted withEtOAc, washed with saturated aqueous NaHCO₃ (×2) and brine. The organiclayer is dried over Na₂SO₄. After concentration, the residue is purifiedby semi-prep HPLC (C-phenyl; 20-60% I/H₂O with 0.1% NH₄OH) to give thetitle compound. MS (ESI) m/z 472.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δppm 10.34 (br. S., 1H), 8.65 (d, J=1.0 Hz, 1H), 8.29 (d, J=9.1 Hz, 1H),8.12 (d, J=3.5 Hz, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.49 (d, J=2.3 Hz,1H), 7.15 (dd, J=8.8, 2.5 Hz, 1H), 7.01-7.06 (m, 2H), 6.80 (d, J=3.8 Hz,1H), 3.86 (s, 3H), 3.71 (s, 2H), 2.29 (s, 3H).

The following compounds are prepared with similar method.

76-E.N-(4-methoxy-3-(trifluoromethyl)phenyl)-5-(6-((methylamino)methyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide

MS (ESI) m/z 472.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.18 (br. S.,1H), 8.65 (d, J=1.0 Hz, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.10 (d, J=3.5 Hz,1H), 7.95 (d, J=2.5 Hz, 1H), 7.90 (dd, J=9.0, 2.7 Hz, 1H), 7.48 (d,J=2.5 Hz, 1H), 7.33 (d, J=9.1 Hz, 1H), 7.13 (dd, J=9.0, 2.4 Hz, 1H),7.03 (d, J=0.8 Hz, 1H), 6.79 (d, J=3.5 Hz, 1H), 3.90 (s, 3H), 3.70 (s,2H), 2.29 (s, 3H).

76-F.5-(6-(((1H-tetrazol-5-yl)methylamino)methyl)pyrimidin-4-yloxy)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

MS (ESI) m/z 528.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.41 (s, 1H),8.84 (s, 1H), 8.31 (d, J=9.1 Hz, 1H), 8.09-8.15 (m, 2H), 7.95-8.05 (m,1H), 7.58 (t, J=9.9 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.23 (s, 1H), 7.16(dd, J=8.8, 2.3 Hz, 1H), 6.83 (d, J=3.8 Hz, 1H), 4.56-4.67 (m, 2H),4.39-4.49 (m, 2H).

EXAMPLE 77 77-A.(±)-5-[6-(1-Hydroxy-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

Methylmagnesium bromide solution (3 M in ether, 20 mL) is added to asolution of 5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (5.0 g 11.7 mmol) in THF (400 mL) at 0°C. The mixture is stirred at that temperature for 3 h before thereaction is then quenched with saturated aqueous NH₄Cl. The product isextracted with EtOAc (3×40 mL) and the combined organic layers arewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue is purified semi-prep HPLC (C18; 30-100% I/H₂Owith 0.1% TFA) to give the title compound as a racemate. MS (ESI) m/z441.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.62 (s, 1H), 8.36 (d, J=8.84Hz, 1H), 8.06 (s, 1H), 7.95 (d, J=3.79 Hz, 1H), 7.90 (d, J=8.08 Hz, 1H),7.58 (t, J=7.83 Hz, 1H), 7.43 (d, J=2.27 Hz, 2H), 7.12 (dd, J=8.97, 2.40Hz, 1H), 7.09 (s, 1H), 6.75 (d, J=3.79 Hz, 1H), 4.75 (d, J=6.57 Hz, 1H),1.45 (d, J=6.57 Hz, 3H).

The racemate Example 77-A is separated via chiral HPLC (ChiralpakOD-column; SFC with 20% MeOH, flow rate: 3.2 mL/min) to give the twocorresponding enantiomers 77-A-1 (R_(t) 3.33 min) and 77-A-2 (R_(t) 4.65min).

77-A-1. 5-[6-(1-Hydroxy-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 443.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.61 (d, J=1.01Hz, 1H), 8.35 (d, J=9.09 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.54 Hz, 1H),7.89 (d, J=8.08 Hz, 1H), 7.56 (t, J=8.08 Hz, 1H), 7.41 (d, J=2.27 Hz,2H), 7.44 (d, J=7.83 Hz, 1H), 7.11 (dd, J=8.97, 2.40 Hz, 1H), 7.09 (s,1H), 6.74 (d, J=3.54 Hz, 1H), 4.76 (q, J=6.65 Hz, 1H), 1.45 (d, J=6.57Hz, 3H).

77-A-2. 5-[6-(1-Hydroxy-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 443.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.62 (s, 1H),8.36 (d, J=9.09 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.79 Hz, 1H), 7.89 (d,J=7.83 Hz, 1H), 7.56 (t, J=7.96 Hz, 1H), 7.44 (d, J=7.83 Hz, 1H), 7.42(d, J=2.27 Hz, 1H), 7.11 (dd, J=8.97, 2.40 Hz, 1H), 7.09 (s, 1H), 6.74(d, J=3.79 Hz, 1H), 4.76 (d, J=6.82 Hz, 1H), 1.45 (d, J=6.57 Hz, 3H).

EXAMPLE 78 5-(6-Formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

To a suspension of5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (310 mg, 0.724 mmol) in DCM (10 mL),DMP (337 mg, 0.795 mmol) is added. The reaction mixture is stirred at rtuntil complete as seen by LCMS (about 1 h). The reaction is quenchedwith saturated aqueous NaHCO₃ and extracted with EtOAc (3×10 mL). Thecombined organic layers are then washed by brine, dried (Na₂SO₄),filtered and concentrated. The crude residue is purified by FCC (0-40%EtOAc/Heptane) to provide the title compound. MS (ESI) m/z 443.1 (M+1);¹H NMR (400 MHz, MeOD) δ ppm 8.84 (d, J=1.01 Hz, 1H), 8.36 (d, J=9.09Hz, 1H), 8.06 (s, 1H), 7.96 (d, J=3.79 Hz, 1H), 7.89 (s, 1H), 7.55-7.60(m, 1H), 7.45 (s, 1H), 7.40 (d, J=1.01 Hz, 2H), 7.44 (d, J=2.53 Hz, 1H),7.13 (dd, J=8.97, 2.40 Hz, 1H), 6.76 (d, J=3.79 Hz, 1H), 2.66 (s, 3H).

EXAMPLE 79 79-A.5-[6-(1-Methylamino-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

To a solution of 5-(6-Formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (200 mg, 0.45 mmol) in MeOH (10 mL),acetic acid (0.1 mL) is added, followed by methylamine in MeOH (0.25mL). The mixture is stirred for 10 min before Na(CN)BH₃ (86 mg, 1.35mmol) is added. The mixture is stirred overnight and then the MeOH isremoved. The residue is partitioned between saturated aqueous NaHCO₃ andEtOAc. The aqueous layer is extracted further with EtOAc (2×30 mL) andthe combined organic layers are washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue is purified withsemi-prep HPLC (C18; 10-100% I/H₂O with 0.1% TFA) to give the titlecompound. MS (ESI) m/z 456.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.66(d, J=1.01 Hz, 1H), 8.35 (d, J=9.09 Hz, 1H), 8.06 (s, 1H), 7.94 (d,J=3.54 Hz, 1H), 7.89 (d, J=8.34 Hz, 1H), 7.56 (t, J=7.96 Hz, 1H), 7.44(d, J=8.08 Hz, 1H), 7.42 (d, J=2.53 Hz, 1H), 7.11 (dd, J=8.97, 2.40 Hz,1H), 7.00 (s, 1H), 6.74 (d, J=3.79 Hz, 1H), 3.71 (d, J=6.82 Hz, 1H),2.28 (s, 3H), 1.36 (d, J=6.82 Hz, 3H).

The following compounds are prepared with similar method.

79-A B5-[6-(1-Cyclopropylamino-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 482.1 (M+1); ¹H NUR (400 MHz, MeOD) δ ppm 8.66 (s, 1H),8.34 (d, J=9.09 Hz, 1H), 8.05 (s, 1H), 7.93 (d, J=3.79 Hz, 1H), 7.89 (d,J=8.08 Hz, 1H), 7.55 (t, J=8.08 Hz, 1H), 7.40 (d, J=2.27 Hz, 1H), 7.43(d, J=7.83 Hz, 1H), 7.09 (dd, J=8.97, 2.40 Hz, 1H), 7.02 (s, 1H), 6.73(d, J=3.79 Hz, 1H), 3.89 (d, J=6.82 Hz, 1H), 1.98 (dd, J=10.48, 2.91 Hz,1H), 1.35 (d, J=6.82 Hz, 3H), 0.34 (tt, J=4.01, 1.93 Hz, 4H).

The racemate is separated via chiral HPLC (Chiralpak AD-column;heptane/EtOH 1:1), flow rate: 14 mL/min) to give the two correspondingenantiomers 79-A B-1 (R_(t) 7.10 min) and 79-A B-2 (R_(t) 7.80 min).

79-A B-1(−)-5-[6-(1-Cyclopropylamino-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 482.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.66 (s, 1H) 8.35(d, J=8.84 Hz, 1H) 8.06 (s, 1H) 7.94 (d, J=3.54 Hz, 1H) 7.89 (d, J=8.34Hz, 1H) 7.56 (t, J=7.96 Hz, 1H) 7.41 (d, J=2.27 Hz, 1H) 7.44 (d, J=7.83Hz, 1H) 7.11 (dd, J=9.09, 2.27 Hz, 1H) 7.02 (s, 1H) 6.74 (d, J=3.79 Hz,1H) 3.89 (d, J=6.82 Hz, 1H) 1.98 (dd, J=10.48, 2.91 Hz, 1H) 1.35 (d,J=6.82 Hz, 3H) 0.31-0.43 (m, 4H).

79-A B-2(+)-5-[6-((S)-1-Cyclopropylamino-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 482.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.66 (d, J=1.01Hz, 1H) 8.35 (d, J=9.09 Hz, 1H) 8.06 (s, 1H) 7.94 (d, J=3.54 Hz, 1H)7.90 (d, J=8.08 Hz, 1H) 7.57 (t, J=8.08 Hz, 1H) 7.42 (d, J=2.27 Hz, 1H)7.44 (d, J=7.83 Hz, 1H) 7.11 (dd, J=8.84, 2.27 Hz, 1H) 7.02 (s, 1H) 6.74(d, J=3.79 Hz, 1H) 3.89 (q, J=6.82 Hz, 1H) 1.98 (dd, J=10.48, 2.91 Hz,1H) 1.35 (d, J=6.82 Hz, 3H) 0.31-0.43 (m, 4H).

EXAMPLE 80 5-(2-Cyano-pyridin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

DIBAL-H (0.75 mL, 1.0 M) is added to a solution of4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester (0.250 g, 0.502 mmol) at 0° C. in DCM (5 mL).After 1 h the solution is allowed to warm to rt. After an additional 1 hthe reaction is quenched with saturated aqueous Rochelle's saltsolution. Workup is done with DCM and saturated aqueous Rochelle's saltsolution. After drying the crude aldehyde is concentrated and taken tonext step as is.

The aldehyde prepared above is taken up in DCM (2 mL) and Et₃N (0.08 mL)and hydroxylamine hydrochloride (0.021 g, 0.300 mmol) is added. After1.5 h, Et₃N (0.9 mL) is added followed by methanesulfonyl chloride(0.025 mL, 0.300 mmol). After stirring overnight the reaction is dilutedwith DCM and washed with brine. The residue is the separated viasemi-prep HPLC (10-90% I/H₂O with 0.1% NH₄OH) to give the titlecompound. MS (ESI) m/z 423.1 (M+1).

EXAMPLE 815-[2-(1-Hydroxy-1-methyl-ethyl)-pyridin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Methyl magnesium iodide (0.30 mL, 3.0 M) is added to a solution of4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylicacid tert-butyl ester (0.150 g, 0.302 mmol) in THF (5 mL) at rt. Afterstirring overnight the reaction is diluted with MeOH (5 mL) and workupdone with DCM and pH 7 buffer. Following concentration the residue isseparated by FCC (80-100% EtOAc/heptane) to give the title compound. MS(ESI) m/z 456.1 (M+1).

EXAMPLE 82 82-A. 5-(6-Chloro-pyrimidin-4-yloxy)-1H-indole

To a solution of 1H-Indol-5-ol (3.0 g, 22.54 mmol) and4,6-dichloro-pyrimidine (3.7 g, 24.8 mmol) in acetonitrile (40 ml), DBU(3.52 ml, 24.8 mmol) is added. The mixture is stirred overnight. Afterremoval of acetonitrile, the residue is partitioned between EtOAc andwater. The aqueous phase is then extracted further with EtOAc. Thecombined organic layers are washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue is then purified by FCC(0-30% EtOAc/Heptane) to provide the title compound. MS (ESI) m/z 246.1(M+1).

82-B. 82-B-14-[6-(1H-Indol-5-yloxy)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester and 82-B-24-[6-(1H-Indol-5-yloxy)-pyrimidin-4-yl]-3,4-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.24 g, 4.0 mmol),5-(6-chloro-pyrimidin-4-yloxy)-1H-indole (750 mg, 3.05 mmol),tetrakis(triphenylphosphine) palladium (106 mg, 0.03 mmol) and potassiumcarbonate (1.26 g, 9.15 mmol) in DMF (15 ml) is degassed and back-filledwith nitrogen in a sealed microwave vial. This mixture is then stirredat 150° C. in microwave reactor for 40 min. After the mixture has cooledto rt, it is diluted with EtOAc/Heptane (8:2) and washed with water (3×)and brine, and the organic layer is dried over anhydrous Na₂SO₄,filtered and concentrated. The residue is then purified by FCC (0-50%EtOAc/Heptane) to provide both title compounds (B-1 and B-2). MS (ESI)m/z 393.1 (M+1).

82-C. 4-[6-(1H-Indol-5-yloxy)-pyrimidin-4-yl]-piperidine-1-carboxylicacid tert-butyl ester

10% Pd/C (20 mg) is added to a solution of the4-[6-(1H-Indol-5-yloxy)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester and4-[6-(1H-Indol-5-yloxy)-pyrimidin-4-yl]-3,4-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (200 mg) in EtOAc (5 mL). The mixture is stirredunder a hydrogen atmosphere (1 atm) overnight before being filtered overCelite® and concentrated in vacuo to give the title compound. MS (ESI)m/z 395.0 (M+1).

EXAMPLE 83 83-A.4-{6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

To a solution of 2,2,6,6-Tetramethyl-piperidine (46.8 mg, 0.33 mmol) in10 mL THF at −78° C. is added n-butyllithium (1.6 M in hexane, 0.22 mL)followed by4-[6-(1H-indol-5-yloxy)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (130 mg, 0.33 mmol) while keep the temperaturebelow −70° C. The reaction mixture is stirred for 10 min, then1-isocyanato-3-trifluoromethyl-benzene (61.7 mg, 0.33 mmol) is added.The reaction mixture is slowly warmed to room temperature and stirred atrt overnight. Concentration under reduced pressure is followed bypartitioning the residue between EtOAc and water. The aqueous layer isextracted further with EtOAc. The combined organic layers are washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue is then purified by FCC (0-50% EtOAc/heptane) to provide thetitle compound. MS (ESI) m/z 579.9 (M+1).

The following compounds are prepared with similar method.

83-B.4-{6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-yl}-3,4-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

MS (ESI) m/z 579.9 (M+1).

83-C.4-{6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-yl}-piperidine-1-carboxylicacid tert-butyl ester

MS (ESI) m/z 581.9 (M+1).

EXAMPLE 84 84-A.5-[6-(1,2,3,6-Tetrahydro-pyridin-4-yl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

TFA (0.5 ml) is added to a solution of4-{6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (160 mg, 0.276 mmol) in DCM (5 mL). The solutionis stirred overnight and then the solvent is removed. The residue isdissolved DCM and washed with saturated aqueous NaHCO₃. The product isextracted further with EtOAc (2×25 mL) and the combined organic layersare washed brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue is then purified by FCC (0-10% 2 M NH₃ inMeOH/DCM) to provide the title compound. MS (ESI) m/z 480.1 (M+1); ¹HNMR (400 MHz, MeOD) δ ppm 8.60 (s, 1H), 8.36 (d, J=8.84 Hz, 1H), 8.06(s, 1H), 7.95 (d, J=3.79 Hz, 1H), 7.91 (s, 1H), 7.58 (t, J=8.21 Hz, 1H),7.45 (s, 1H), 7.42 (d, J=2.27 Hz, 1H), 7.12 (dd, J=8.97, 2.40 Hz, 1H),7.00 (dt, J=3.35, 1.74 Hz, 1H), 6.98 (s, 1H), 6.75 (d, J=3.79 Hz, 1H),3.70-3.75 (m, 2H), 3.07 (t, J=5.81 Hz, 2 H), 1.87 (ddd, J=6.44, 3.41,3.28 Hz, 2H).

The following compounds are prepared with similar method.

84-B.5-[6-(1,2,3,4-Tetrahydro-pyridin-4-yl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 480.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.59 (d, J=1.01Hz, 1H), 8.63 (d, J=1.01 Hz, 1H), 8.35 (d, J=8.34 Hz, 1H), 8.06 (s, 1H),7.94 (d, J=2.78 Hz, 1H), 7.54-7.60 (m, 2 H), 7.41 (d, J=1.77 Hz, 2H),7.44 (d, J=7.83 Hz, 1H), 7.11 (dd, J=9.09, 1.52 Hz, 1H), 6.84 (s, 1H),6.74 (d, J=3.79 Hz, 1H), 4.33-4.35 (m, 1H), 3.03-3.21 (m, 2H), 2.76 (dt,J=11.37, 2.15 Hz, 2H).

84-C. 5-(6-Piperidin-4-yl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 482.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.60 (s, 1H),8.35 (d, J=8.84 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.79 Hz, 1H), 7.89 (d,J=8.08 Hz, 1H), 7.57 (t, J=8.08 Hz, 1H), 7.40 (d, J=2.27 Hz, 1H), 7.44(d, J=7.83 Hz, 1H), 7.10 (dd, J=8.97, 2.40 Hz, 1H), 6.85 (s, 1H), 6.74(d, J=3.79 Hz, 1H), 3.13 (d, J=12.63 Hz, 2H), 2.70 (td, J=12.44, 2.40Hz, 2H), 2.66-2.83 (m, 1H), 1.89 (d, J=12.13 Hz, 2H), 1.69 (dd, J=12.63,3.79 Hz, 2H).

EXAMPLE 85(±)-5-{6-[Hydroxy-(1-methyl-1H-imidazol-2-yl)-methyl]-pyrimidin-4-yloxy}indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of 1-methyl-1H-imidazole (77 mg, 0.94 mmol) in 5 mL THF at−78° C. is added n-butyllithium (1.6 M in hexane, 0.44 mL). The solutionis stirred at −78° C. for 1 h. Then, a solution of5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (200 mg, 0.47 mmol) in THF (5 mL) isadded. The reaction is allowed to warm up to rt and stir overnight. Atthat time the reaction is quenched with water and then extracted withEtOAc (3×25 mL). The combined organic layers are washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue isthen purified with semi-prep HPLC (C18; 30-100% I/H₂O with 0.1% TFA) togive the title compound. The fractions are pooled and the pH is adjustedto 9 with sodium bicarbonate. The product is extracted with EtOAc. Theorganic layer is washed with brine, dried over anhydrous sodium sulfate,and filtered. The filtrate is concentrated to give the title compound.MS (ESI) m/z 509.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.59 (d, J=1.01Hz, 1H), 8.36 (d, J=9.09 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.79 Hz, 1H),7.90 (d, J=7.83 Hz, 1H), 7.57 (m, 2H), 7.46 (d, J=2.02 Hz, 1H), 7.29 (s,1H), 7.16 (dd, J=8.97, 2.40 Hz, 1H), 7.05 (d, J=1.26 Hz, 1H), 6.85 (d,J=1.26 Hz, 1H), 6.75 (d, J=3.54 Hz, 1H), 5.91 (s, 1H), 3.72 (s, 3H).

EXAMPLE 86 86-A.N-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(6-(methylsulfonylmethyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide

To a solution of(6-(1-(4-fluoro-3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-yl)methylmethanesulfonate (0.22 g, 0.42 mmol) in 5 mL of THF and 3 mL of DMF, Nat(0.095 g, 0.63 mmol) is added followed by DIEA (0.11 mL, 0.63 mmol) andsodium methanesulfinate (0.129 g, 1.26 mmol). The mixture is stirred atrt for 2 h and then diluted with EtOAc, washed with saturated NaHCO₃(×2), brine and the organic layer is dried over Na₂SO₄. Afterconcentration the residue is purified by FCC (20-90% EtOAc/heptane) andthen semi-prep HPLC (22-65% I/H₂O with 0.1% NH₄OH) to give the titlecompound. MS (ESI) m/z 509.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.38 (br. S., 1H), 8.78 (d, J=1.0 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H),8.06-8.17 (m, 2H), 7.97-8.05 (m, 1H), 7.58 (t, J=9.7 Hz, 1H), 7.52-7.54(m, 1H), 7.21 (d, J=1.0 Hz, 1H), 7.18 (dd, J=9.0, 2.4 Hz, 1H), 6.82 (dd,J=3.7, 0.6 Hz, 1H), 4.70 (s, 2H), 3.11 (s, 3H).

The following compounds are prepared with similar method.

86-B.4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

MS (ESI) m/z 488.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.78 (d, J=1.01Hz, 1H), 8.21 (d, J=4.04 Hz, 1H), 8.13 (d, J=9.09 Hz, 1H), 7.38 (d,J=1.01 Hz, 1H), 7.34 (s, 1H), 6.91 (d, J=3.79 Hz, 1H), 6.68 (s, 1H),4.74 (s, 2H), 3.14 (s, 3H), 1.35 (s, 9H).

EXAMPLE 87 87-A.[6-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-yl]-methanol

In a 20 mL microwave vial is placed5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole(2.59 g, 7.13 mmol) in methane sulfonic acid (15 ml) and the solution isheated in a microwave reactor at 100° C. for 5 min. The reaction is thendiluted with 250 mL EtOAc and saturated aqueous NaHCO₃. The aqueouslayer is washed with EtOAc (4×100 mL). The organic phases are combined,washed with (2×150 mL) water, followed by (1×60 mL brine), dried overNa₂SO₄, and concentrated in vacuo. The residue is purified via FCC(0-20% MeOH/DCM) to give the title compound. MS (ESI) m/z 274.1 (M+1).

87-B.4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-1H-indole

[6-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-yl]-methanol (1 g,3.66 mmol) is placed in DCM (40 mL). Methanesulfonyl chloride (0.34 mL,4.39 mmol) and DIPEA (0.89 mL, 5.12 mmol) are added and then after 15min the reaction is diluted with water and extracted with DCM. Theorganic phase is washed with brine, dried over Na₂SO₄, and concentratedin vacuo. The resulting methanesulfonic acid6-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl ester isdissolved in DMF (10 mL) and sodium methanesulfinate (1.12 g, 11.0 mmol)is added and the reaction is stirred at rt for 18 h. The reaction ispartitioned between H₂O and ethyl acetate. The organic phase is washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residue ispurified via FCC (0-10% MeOH/DCM) to give the title compound. MS (ESI)m/z 336.0 (M+1)

87-C.4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-1H-indole(250 mg, 0.745 mmol) in THF (10 mL) is cooled to −78° C. and a 1 Msolution of LiHMDS in THF (1.86 mL, 1.86 mmol) is added. After 12 min1-isocyanato-3-(trifluoromethyl)-benzene (0.12 mL, 0.895 mmol) is addedand the reaction is allowed to stir at −78° C. After 1 h the reaction isquenched with saturated aqueous NH₄Cl and then extracted with (3×100 mL)EtOAc. The organic phases are combined and washed with brine, dried overNa₂SO₄, and concentrated in vacuo. The residue is purified FCC (0-3%MeOH/DCM) to provide4-fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 523.1 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.99 (s, 1H), 8.77 (d, J=1.01 Hz, 1H), 8.12(s, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 7.53 (d, J=9.35 Hz, 2H), 7.36 (d,J=1.01 Hz, 1H), 7.20 (d, J=7.33 Hz, 1H), 6.64 (s, 1H), 4.73 (s, 2H),3.13 (s, 3H), 2.59 (s, 3H).

The following compounds are prepared with similar method.

87-D. 5-(6-Methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (2-fluoro-3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 509.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.78 (d,J=1.01 Hz, 1H), 8.27 (d, J=8.84 Hz, 1H), 8.11 (d, J=3.54 Hz, 1H), 7.94(s, 1H), 7.71 (s, 1H), 7.47-7.54 (m, 2H), 7.16-7.21 (m, 2H), 6.83 (d,J=3.79 Hz, 1H), 4.69 (s, 2H), 3.11 (s, 3H).

87-E.4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 509.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (br. S.,1H), 8.79 (s, 1H), 8.09-8.24 (m, 3H), 7.97 (d, J=8.08 Hz, 1H), 7.66 (t,J=7.96 Hz, 1H), 7.51 (d, J=7.83 Hz, 1H), 7.38 (s, 1H), 7.33 (t, J=8.34Hz, 1H), 6.94 (d, J=3.79 Hz, 1H), 4.74 (s, 2H), 3.14 (s, 3H).

EXAMPLE 88 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-methyl-pyridin-3-yl)-amide

Urea prepared by analogy to Example 51-A by coupling Example 14-A with3-amino-5-methylpyridine followed by removal of the benzyl protectinggroup as described in Example 16-A. MS (ESI) m/z 376.0 (M+1).

EXAMPLE 891-((6-(1-(4-fluoro-3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-yl)methyl)piperidine-4-carboxylicacid

To a solution of methyl1-((6-(1-(4-fluoro-3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-yl)methyl)piperidine-4-carboxylate(0.13 g, 0.228 mmol) in 40 mL of THF/H₂O (3:1), 2 M aq LiOH solution(0.23 mL) is added. The mixture is stirred at rt for 3.5 h before beingconcentrated and purified by semi-prep HPLC (12-48% CAN/H₂O with 0.1%TFA) to give the title compound. MS (ESI) m/z 558.1 (M+1); ¹H NMR (400MHz, DMSO-d₅) δ ppm 10.43 (s, 1H), 9.93-10.12 (m, 1H), 8.88 (s, 1H),8.32 (d, J=9.1 Hz, 1H), 8.08-8.17 (m, 2H), 7.96-8.06 (m, 1H), 7.58 (t,J=9.9 Hz, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.25 (br. S., 1H), 7.17 (dd,J=9.0, 2.4 Hz, 1H), 6.83 (d, J=3.5 Hz, 1H), 4.39-4.60 (m, 2H), 3.45-3.57(m, 2H), 2.98-3.17 (m, 2H), 1.95-2.14 (m, 3H), 1.73-1.91 (m, 2H)

EXAMPLE 90 90-A.(±)-5-(6-(benzyloxymethyl)pyrimidin-4-yloxy)-N-(4-methoxy-3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a solution of 5-(6-(benzyloxymethyl)pyrimidin-4-yloxy)-1H-indole (0.8g, 2.41 mmol) in 35 mL of DCE, CDI (1.17 g, 7.24 mmol) is added followedby TEA (1 mL, 7.24 mmol). Mixture is stirred at rt overnight and then4-methoxy-3-(trifluoromethyl)aniline (1.38 g, 7.24 mmol) is addedfollowed by stirring for 4 days. The reaction is diluted with DCM,washed with saturated aqueous NaHCO₃ (×2), brine, and the organic layeris dried over Na₂SO₄. After concentration, the residue is purified byFCC (5-60% EtOAc/heptane) to give the title compound. MS (ESI) m/z 549.1(M+1).

90-B.5-(6-((2-Hydroxyethylamino)methyl)pyrimidin-4-yloxy)-N-(4-methoxy-3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

Prepared in similar manner to that described Example 19. MS (ESI) m/z502.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.15 (br. S., 1H), 8.65(d, J=1.0 Hz, 1H), 8.28 (d, J=9.1 Hz, 1H), 8.10 (d, J=3.8 Hz, 1H), 7.95(d, J=2.8 Hz, 1H), 7.91 (dd, J=8.8, 2.5 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H),7.33 (d, J=9.1 Hz, 1H), 7.13 (dd, J=8.8, 2.3 Hz, 1H), 7.09 (s, 1H), 6.79(d, J=3.8 Hz, 1H), 3.90 (s, 3H), 3.78 (s, 2H), 3.45 (t, J=5.7 Hz, 2H),2.59 (t, J=5.8 Hz, 2H).

EXAMPLE 91 91-A.5-[6-(Cyano-trimethylsilanyloxy-methyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of 5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (200 mg, 0.471 mmol) andmethyl-triphenyl-phosphonium iodide (19 mg, 0.05 mmol) in DCM (5 mL),TMSCN (0.063 mL, 0.471 mmol) is added via syringe. The mixture isstirred for 3 h, then it is diluted with DCM (20 mL), washed with water,brine, and the organic layer is dried over Na₂SO₄, filtered, andcondensed to obtain the title compound that is used in the next stepwithout further purification. MS (ESI) m/z 525.9 (M+1).

91-B.(±)-5-[6-(2-Amino-1-hydroxy-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Ranney-Ni (20 mg) is washed with MeOH (3×5 mL) before a solution of(±)-5-[6-(cyano-trimethylsilanyloxy-methyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (100 mg, 0.19 mmol) in MeOH (5 mL)and THF (3 mL) is added. The mixture is stirred under H₂ atmosphere(ballon) overnight. The mixture is filtered through Celite® and thefiltrate is concentrated. The residue is then separated by FCC (0-10%MeOH/EtOAc) to provide the title compound. MS (ESI) m/z 458.1 (M+1); ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.60-8.70 (m, 1H), 8.36 (d, J=8.59 Hz, 1H),8.06 (br. S., 1H), 7.90 (d, J=7.58 Hz, 1H), 7.95 (d, J=3.28 Hz, 2H),7.73 (d, J=4.55 Hz, 1H), 7.57 (t, J=7.83 Hz, 1H), 7.37-7.47 (m, 3H),7.12 (d, J=8.59 Hz, 2H), 7.04 (s, 1H), 6.75 (br. S., 1H), 4.89 (d,J=5.05 Hz, 1H), 3.67 (dd, J=12.25, 7.71 Hz, 2H).

EXAMPLE 92 92-A.5-[6-((S)-2-Carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

To a solution of 5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (60 mg, 0.141 mmol) in MeOH (5 mL),AcOH (0.1 mL) is added followed by (S)-pyrrolidine-2-carboxylic acidamide (19 mg, 0.169 mmol). The mixture is stirred for 10 min beforeNaBH₃(CN) is added. The resulting mixture is stirred overnight. At thatpoint the mixture is quenched with sat aqueous sodium bicarbonate. Theproduct is extracted with EtOAc (3×). The combined organic layers arewashed with water, and brine, and then dried over Na₂SO₄, filtered, andcondensed. The residue is then separated by FCC (0-10%, 2M ammonia inMeOH/DCM) to provide the title compound. MS (ESI) m/z 524.9 (M+1); ¹HNMR (400 MHz, MeOD) δ ppm 8.63 (s, 1H), 8.34 (d, J=9.09 Hz, 1H), 8.06(s, 1H), 7.94 (d, J=3.79 Hz, 1H), 7.89 (d, J=7.83 Hz, 1H), 7.57 (t,J=8.08 Hz, 1H), 7.41 (d, J=2.53 Hz, 1H), 7.44 (d, J=8.59 Hz, 1H),7.07-7.14 (m, 1H), 7.12 (d, J=2.27 Hz, 1H), 6.74 (d, J=3.54 Hz, 1H),3.94 (d, J=14.65 Hz, 1H), 3.66 (d, J=14.65 Hz, 1H), 3.23 (dd, J=9.73,5.18 Hz, 1H), 3.12 (dd, J=8.72, 4.67 Hz, 1H), 2.46 (t, J=8.21 Hz, 1H),2.23 (td, J=9.09, 4.29 Hz, 1H), 1.79-1.91 (m, 3H).

The following compounds are prepared with similar method.

92-B.5-[6-(I-2-Carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 524.9 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.63 (s, 1H),8.34 (d, J=9.09 Hz, 1H), 8.05 (s, 1H), 7.93 (d, J=3.79 Hz, 1H), 7.89 (d,J=8.08 Hz, 1H), 7.56 (t, J=7.96 Hz, 1H), 7.40 (d, J=2.27 Hz, 1H), 7.43(d, J=7.83 Hz, 1H), 7.06-7.13 (m, 1H), 7.11 (d, J=2.53 Hz, 1H), 6.73 (d,J=3.54 Hz, 1H), 3.93 (d, J=14.65 Hz, 1H), 3.65 (d, J=14.65 Hz, 1H), 3.22(dd, J=9.73, 5.18 Hz, 1H), 3.10 (d, J=4.55 Hz, 1H), 2.44 (t, J=8.08 Hz,1H), 2.21 (dd, J=7.83, 2.78 Hz, 1H), 2.15-2.36 (m, 1H), 1.78-1.92 (m,3H).

92-C.5-[6-((S)-2-Ethylcarbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 552.9 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.66 (s, 1H),8.36 (d, J=8.84 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J=3.79 Hz, 1H), 7.90 (d,J=6.57 Hz, 1H), 7.57 (t, J=7.96 Hz, 1H), 7.42 (d, J=2.27 Hz, 2H), 7.11(dd, J=8.97, 2.40 Hz, 1H), 7.07 (s, 1H), 6.75 (d, J=3.79 Hz, 1H), 3.88(d, J=14.40 Hz, 1H), 3.69 (d, J=14.40 Hz, 1H), 3.18 (qd, J=7.28, 1.14Hz, 2H), 3.09-3.27 (m, 2H), 2.44-2.52 (m, 1H), 2.21 (td, J=9.09, 4.04Hz, 1H), 1.74-1.87 (m, 3H), 1.07 (t, J=7.33 Hz, 3H).

EXAMPLE 93 93-A.(±)-3-({6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylicacid tert-butyl ester

To the solution of methanesulfonic acid(±)-6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethylester (80 mg, 0.158 mmol) in THF (5 mL),3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (88 mg, 0.474mmol) and diisopropylethylamine (61 mg, 0.474 mmol) are added. Theresulting solution is stirred at 60° C. overnight. After cooling to rt,the reaction mixture is diluted with EtOAc and washed with water andthen brine. The organic layer is dried with anhydrous Na₂SO₄, filtered,and condensed. The residue is purified by FCC (0-10% MeOH/DCM) toprovide the title compound. MS (ESI) m/z 597.2 (M+1).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 93-B

(MeOD) δ ppm 8.59 (s, 1 H), 8.39 (br. S., 1 H), 8.14 (d, J = 8.84 Hz, 1H), 7.72 (s, 1 H), 7.67 (d, J = 8.08 Hz, 1 H), 7.52 (d, J = 3.79 Hz, 1H), 7.28-7.39 (m, 1 H), 7.23 (br. S., 1 H), 6.95-7.01 (m, 2 H), 6.47 (d,J = 2.78 Hz, 1 H), 3.63 (d, J = 8.34 Hz, 2 H), 2.79-2.91 (m, 3 H), 2.65(d, J = 6.06 Hz, 1 H), 2.53 (q, J = 7.75 Hz, 1 H), 1.99 (t, J = 6.95 Hz,2 H), 1.35 (s, 9 H). 582.2 93-C

(MeOD) δ ppm 8.63 (s, 1 H) 8.34 (d, J = 9.09 Hz, 1 H) 8.06 (s, 1 H) 7.94(d, J = 3.79 Hz, 1 H) 7.89 (d, J = 7.83 Hz, 1 H) 7.57 (t, J = 8.08 Hz, 1H) 7.44 (d, J = 8.59 Hz, 1 H) 7.07-7.14 (m, 3 H) 6.74 (d, J = 3.54 Hz, 1H) 4.85 (s, 2 H) 3.94 (m, , 1 H) 3.66 (m, 1 H) 3.23 (m, 1 H) 3.12 (m, 1H) 2.45 (m, 1 H) 2.23 (m, 1 H) 2.02 (s, 3 H) 1.79-1.91 (m, 4 H) 553.293-D

(MeOD) δ ppm 8.64 (d, J = 1.01 Hz, 1 H) 8.35 (d, J = 9.09 Hz, 1 H) 8.06(s, 1 H) 7.95 (d, J = 3.79 Hz, 1 H) 7.90 (d, J = 7.83 Hz, 1 H) 7.57 (t,J = 7.96 Hz, 1 H) 7.42 (d, J = 2.02 Hz, 1 H) 7.44 (d, J = 7.83 Hz, 1 H)7.12 (dd, J = 8.97, 2.40 Hz, 1 H) 7.07 (d, J = 1.01 Hz, 1 H) 6.75 (d, 7= 3.79 Hz, 1 H) 3.77 (d, J = 4.55 Hz, 2 H) 2.98 (m, 1 H) 2.89 (m, 1 H)2.68-2.79 (m, 3 H) 2.04 (m, 2 H) 524.9 93-E

(MeOD) δ ppm 8.63 (d, J = 1.01 Hz, 1 H) 8.35 (d, J = 9.09 Hz, 1 H) 8.06(s, 1 H) 7.94 (d, J = 3.79 Hz, 1 H) 7.90 (d, J = 8.08 Hz, 1 H) 7.57 (t,J = 7.96 Hz 1 H) 7.42 (d, J = 2.53 Hz, 1 H) 7.44 (d, J = 7.83 Hz, 1 H)7.11 (dd, J = 8.97, 2.40 Hz, 1 H) 7.04 (d, J = 1.01 Hz, 1 H) 6.74 (d, J= 3.79 Hz, 1 H) 3.86 (s, 2 H) 3.51 (s, 2 H) 2.95 (d, J = 15.41 Hz, 6 H)512.9 93-F

(MeOD) δ ppm 8.60 (d, J = 1.01 Hz, 1 H) 8.35 (d, J = 9.09 Hz, 1 H) 8.06(s, 1 H) 7.88=7.95 (m, 1 H) 7.94 (d, J = 3.54 Hz, 1 H) 7.57 (t, J = 8.08Hz, 1 H) 7.42 (d, J = 2.53 Hz, 1 H) 7.44 (d, J = 7.83 Hz, 1 H) 7.11 (t,J = 4.42 Hz, 1 H) 7.12 (d, J = 8.84 Hz, 1 H) 6.74 (d, J = 3.79 Hz, 1 H)3.96 (s, 1 H) 3.74 (d, J = 15.16 Hz, 1 H) 3.63 (s, 3 H) 3.44 (dd, J =8.84, 5.56 Hz, 1 H) 3.08 (ddd, J = 8.97, 6.69, 4.29 Hz, 1 H) 2.54 (d, J= 8.84 Hz, 1 H) 2.15 (dd, J = 11.37, 2.78 Hz, 1 H) 1.81-1.96 (m, 3 H).539.8 93-G

(MeOD) δ ppm 8.60 (d, J = 1.01 Hz, 1 H) 8.35 (d, J = 8.84 Hz, 1 H) 8.05(s, 1 H) 7.93 (d, J = 3.79 Hz, 1 H) 7.89 (d, J = 8.08 Hz, 1 H) 7.56 (t,J = 8.08 Hz, 1 H) 7.41 (d, J = 2.27 Hz, 1 H) 7.43 (d, J = 7.83 Hz, 1 H)7.13 (s, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1 H) 6.73 (d, J = 3.79 Hz, 1H) 4.35 (dd, J = 8.97, 2.65 Hz, 1 H) 4.02 (d, J = 15.66 Hz, 1 H) 3.83(s, 1 H) 3.73 (t, J = 7.83 Hz, 1 H) 3.64 (s, 3 H) 3.34 (d, J = 4.80 Hz,1 H) 2.53 (dd, J = 10.11, 3.54 Hz, 1 H) 2.04-2.18 (m, 2 H). 555.9 93-H

(MeOD) δ ppm 8.66 (s, 1 H) 8.36 (d, J = 8.84 Hz, 1 H) 8.06 (s, 1 H) 7.95(d, J = 3.79 Hz, 1 H) 7.90 (d, J = 6.57 Hz, 1 H) 7.57 (t, J = 7.96 Hz, 1H) 7.42 (d, J = 2.27 Hz, 2 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1 H) 7.07 (s,1 H) 6.75 (d, J = 3.79 Hz, 1 H) 3.88 (d, J = 14.40 Hz, 1 H) 3.69 (d, J =14.40 Hz, 1 H) 3.18 (qd, J = 7.28, 1.14 Hz, 2 H) 3.09-3.27 (m, 2 H)2.44-2.52 (m, 1 H) 2.21 (td, J = 9.09, 4.04 Hz, 1 H) 1.74-1.87 (m, 3 H)1.07 (t, J = 7.33 Hz, 3 H) 552.9

EXAMPLE 94 94-A.(±)-5-[6-(Pyrrolidin-3-ylaminomethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

(±)-3-({6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylicacid tert-butyl ester (20 mg, 3.30 mmol) is stirred in a solution of DCM(2 mL) and TFA (0.5 mL) overnight. After removal of solvents, theresidue is quenched with saturated aqueous sodium bicarbonate. Themixture is then extracted with EtOAc (3×) and the combined organiclayers are washed with water, brine, dried with Na₂SO₄, filtered, andcondensed. The residue is purified by FCC (0-10% 2 M NH₃ in MeOH/DCM) toprovide the title compound. MS (ESI) m/z 496.8 (M+1); ¹H NMR (400 MHz,MeOD) δ ppm 8.65 (s, 1H), 8.36 (d, J=8.84 Hz, 1H), 8.06 (s, 1H), 7.95(d, J=3.54 Hz, 1H), 7.88 (s, 1H), 7.57 (t, J=7.83 Hz, 1H), 7.44 (d,J=7.83 Hz, 1H), 7.42 (d, J=2.27 Hz, 1H), 7.03-7.13 (m, 2H), 6.75 (d,J=3.79 Hz, 1H), 3.80-3.85 (m, 2H), 2.81-3.02 (m, 3H), 2.52-2.75 (m, 2H),2.19-2.35 (m, 2H).

The following compounds are prepared with similar method.

94-B.5-{6-[(1S,4S)-1-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)methyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 509.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.61 (d, J=1.01Hz, 1H), 8.35 (d, J=8.84 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.54 Hz, 1H),7.89 (d, J=8.59 Hz, 1H), 7.56 (t, J=7.96 Hz, 1H), 7.41 (d, J=2.27 Hz,1H), 7.40-7.45 (m, 1H), 7.10 (dd, J=8.97, 2.40 Hz, 1H), 7.06 (s, 1H),6.73 (d, J=3.79 Hz, 1H), 3.81 (d, J=13.39 Hz, 1H), 3.75-3.87 (m, 1H),3.57 (s, 1H), 3.43 (s, 1H), 3.09 (d, J=10.61 Hz, 1H), 2.87 (dd, J=9.85,2.53 Hz, 1H), 2.77 (dd, J=10.48, 2.40 Hz, 1H), 2.57 (d, J=9.85 Hz, 1H),1.85 (d, J=10.36 Hz, 1H), 1.58 (d, J=9.60 Hz, 1H).

EXAMPLE 95(±)-5-[6-(3-Carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

3-Carbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 1.03mmol) is dissolved in DCM (5 mL). TFA (2 mL, 26.0 mmol) is added and thereaction is allowed to stir at rt overnight. The solvent is removed invacuo and THF (5.0 mL) is added followed by methanesulfonic acid6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethylester (0.347 g, 0.685 mmol) and DIEA (0.60 mL, 3.42 mmol). The reactionis heated at 60° C. for 19 h. The solvent is removed in vacuo and theresidue separated by FCC (0-15%, 10% NH₃MeOH/DCM) to provide(±)-5-[6-(3-carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 524.9 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.41 (s, 1H), 8.72 (s, 1H), 8.30 (d, J=8.84Hz, 1H), 8.14 (d, J=3.79 Hz, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.65 (t,J=8.08 Hz, 1H), 7.51 (d, J=2.53 Hz, 2H), 7.16 (dd, J=8.84, 2.27 Hz, 1H),7.12 (s, 1H), 6.81 (d, J=3.54 Hz, 1H), 3.63 (br. S., 1H), 3.14 (d,J=7.33 Hz, 1H), 2.94 (br. S., 1H), 1.99 (br. S., 1H), 1.25 (d, J=6.06Hz, 6H).

EXAMPLE 96 96-A.5-[7-(2-Hydroxy-ethyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

A solution of5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide, Example 33-C, (150 mg, 0.33mmol), 2-bromoethanol (28 uL, 0.40 mmol) and TEA (0.1 mL, 0.66 mL) in I(3 mL) is heated at 85° C. for 24 h. The reaction is then concentratedin vacuo and the residue separated via semi-prep HPLC (C18; 10-100%I/H₂O with 0.1% NH₄OH) to give the title compound. MS (ESI) m/z 498.1(M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.38 (s, 1H), 8.33 (d, J=8.8 Hz,1H), 8.06 (s, 1H), 7.93 (d, J=3.8 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.58(t, J=8.1 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.11(dd, J=9.0, 2.4 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 3.81 (t, J=5.8 Hz, 2H),3.75 (s, 2H), 2.96 (s, 4H), 2.79 (t, J=5.8 Hz, 2H).

The following compounds are prepared with similar method.

96-B.4-Fluoro-5-[7-(3-methoxy-propyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

4-Fluoro-2-methyl-5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (250 mg, 0.515 mmol) is dissolvedin DMF (5 mL) and 1-Bromo-3-methoxypropane (79 mg, 0.515 mmol) and DIEA(0.11 mL, 0.618 mmol) are added. The reaction is stirred at rt for 72 h.At that point the reaction is diluted with EtOAc and H₂O. The organiclayer is washed with water and brine before being dried over Na₂SO₄,filtered, concentrated. The residue is separated by FCC (20-100%EtOAc/heptane) to give the title compound. MS (ESI) m/z 557.9 (M+1).

EXAMPLE 97 97-A.(±)-3-(Methanesulfonyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of(±)-3-({6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylicacid tert-butyl ester (20 mg, 0.033 mmol) in THF (5 mL) methanesulfonylchloride (6.0 mg, 0.05 mmol) and TEA (7 mg, 0.066 mmol) are added at 0°C. After 30 min, the mixture is diluted with EtOAc, washed with water,brine, and then the organic layer is dried over Na₂SO₄, filtered, and,condensed. The residue is separated by FCC (0-10%, 2 M NH₃ in MeOH/DCM)to provide the title compound. MS (ESI) m/z 674.1 (M+1).

The following compounds are prepared with similar method.

97-B.5-[6-((1R,4S)-5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 587.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.61 (d, J=5.05Hz, 1H), 8.35 (d, J=8.84 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.79 Hz, 1H),7.89 (d, J=8.08 Hz, 1H), 7.57 (t, J=8.08 Hz, 1H), 7.42 (d, J=1.77 Hz,1H), 7.41-7.46 (m, 1H), 7.04-7.14 (m, 2H), 6.74 (d, J=3.79 Hz, 1H), 4.63(s, 1H), 4.26 (s, 1H), 3.87 (d, J=5.31 Hz, 1H), 3.61 (s, 1H), 3.45 (d,J=9.60 Hz, 1H), 3.24 (dd, J=9.35, 2.27 Hz, 1H), 2.88 (s, 3H), 2.82-2.91(m, 3H), 1.93 (d, J=10.61 Hz, 1H).

EXAMPLE 98 98-A.(±)-3-(Acetyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of(±)-3-({6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylicacid tert-butyl ester (60 mg, 0.10 mmol) in THF (5 mL) acetyl chloride(12 mg, 0.15 mmol) and TEA (20 mg, 0.2 mmol) are added at 0° C. After 30min, the mixture is diluted with EtOAc, washed with water, brine, andthe organic layer is dried over Na₂SO₄, filtered, and condensed. Theresidue is separated by FCC (0-10%, 2 M NH₃ in MeOH/DCM) to provide thetitle compound. MS (ESI) m/z 638.1 (M+1).

The following compounds are prepared with similar method.

98-B.5-[6-((1R,4S)-5-Acetyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 551.1 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.62 (d, J=4.55Hz, 1H), 8.37 (dd, J=8.97, 4.93 Hz, 1H), 8.07 (s, 1H), 7.96 (dd, J=3.79,2.27 Hz, 1H), 7.90 (d, J=8.84 Hz, 1H), 7.58 (t, J=8.08 Hz, 1H), 7.43 (s,1H), 7.44 (t, J=6.06 Hz, 1H), 7.12 (ddd, J=8.97, 3.79, 2.40 Hz, 1H),7.07 (d, J=4.55 Hz, 1H), 6.76 (t, J=3.41 Hz, 1H), 4.66 (s, 1H), 3.86 (s,2H), 3.62 (s, 1H), 3.56 (dd, J=10.74, 6.95 Hz, 1H), 3.24 (dd, J=11.49,1.89 Hz, 1H), 2.71 (dd, J=13.89, 9.85 Hz, 1H), 2.08 (s, 3H), 1.91-2.01(m, 3H).

EXAMPLE 99 99-A.5-(6-((1H-tetrazol-1-yl)methyl)pyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a solution of(6-(1-(3-methoxy-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-yl)methylmethanesulfonate (1.05 mmol) in 4 mL of THF, a solution of 1H-tetrazole(0.221 g, 3.14 mmol) in 3 mL of DMF is added followed by Cs₂CO₃ (1.02 g,3.14 mmol) and NaI (0.472 g, 3.14 mmol). The mixture is stirred at rtfor 1 h and then diluted with EtOAc, washed with saturated NaHCO₃ (×2),brine and the organic layer is dried over Na₂SO₄. After concentration,the residue is purified by FCC (5-90% EtOAc/heptane) to provide tworegioisomeric tetrazoles Example 99A and 99B.

MS (ESI) m/z 511.0 (M+1), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.35 (s, 1H),9.53 (s, 1H), 8.68 (d, J=0.8 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.12 (d,J=3.8 Hz, 1H), 7.70 (s, 1H), 7.60 (t, J=2.0 Hz, 1H), 7.51 (d, J=2.5 Hz,1H), 7.14 (s, 2H), 6.99-7.04 (m, 1H), 6.81 (d, J=3.5 Hz, 1H), 5.89 (s,2H), 3.86 (s, 3H)

99-B.5-(6-((2H-Tetrazol-2-yl)methyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-methoxy-5-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 511.4 (M+1), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.35 (s, 1H),9.04 (s, 1H), 8.67 (d, J=1.0 Hz, 1H), 8.24-8.35 (m, 1H), 8.08-8.17 (m,1H), 7.67-7.74 (m, 1H), 7.57-7.63 (m, 1H), 7.52 (d, J=2.5 Hz, 1H),7.15-7.19 (m, 1H), 7.11 (s, 1H), 7.01-7.05 (m, 1H), 6.79-6.83 (m, 1H),6.13 (s, 2H), 3.86 (s, 3H).

EXAMPLE 100(±)-5-{6-[(Acetyl-pyrrolidin-3-yl-amino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

(±)-3-(Acetyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylicacid tert-butyl ester (30 mg, 0.056 mmol) is stirred in a solution ofDCM (2 mL) and TFA (0.5 mL) overnight. After removal of the solvents,the residue is quenched with saturated aqueous sodium bicarbonate. Themixture is extracted with EtOAc (3×). The combined organic layers arewashed with water and brine and the organic layer is dried with Na₂SO₄,filtered, and condensed. The residue is then separated by FCC (0-10%, 2mol NH₃ in MeOH/DCM) to provide the title compound. MS (ESI) m/z 538.9(M+1).

EXAMPLE 101 101-A.(±)-5-{6-[(Methanesulfonyl-pyrrolidin-3-yl-amino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

(±)-3-(Methanesulfonyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylicacid tert-butyl ester (12 mg, 0.018 mmol) is stirred in a solution ofDCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, theresidue is quenched with saturated aqueous sodium bicarbonate. Themixture is extracted with EtOAc (3×). The combined organic layers arewashed with water and brine and the organic layer is dried with Na₂SO₄,filtered, and condensed. The residue is then separated by FCC (0-10%, 2M NH₃ in MeOH/DCM) to provide the title compound. MS (ESI) m/z 574.8(M+1).

EXAMPLE 102 102-A.(±)-5-(Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

Prepared with similar method to Example 57. MS (ESI) m/z 433.0 (M+1); ¹HNMR (400 MHz, MeOD) δ ppm 8.50 (s, 1H) 8.35 (d, J=8.84 Hz, 1H) 7.90 (d,J=3.79 Hz, 1H) 7.41 (d, J=2.27 Hz, 1H) 7.12 (dd, J=8.97, 2.40 Hz, 1H)6.73 (d, J=3.79 Hz, 1H) 6.66 (s, 1H) 4.70 (q, J=6.48 Hz, 1H) 4.10-4.16(m, 2H) 1.59 (d, J=6.57 Hz, 3H) 1.38 (s, 9H).

Chiral HPLC (Column IA, 40% acetonitrile, 60% isopropanol) provides thetwo enantiomers 102-A-1 and 102-A-2:

102-A-1:(−)-5-(Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

R_(t)=5.44 min; MS (ESI) mz 433.0 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ ppm8.54 (s, 1H) 8.30 (d, J=9.09 Hz, 1H) 8.16 (d, J=3.79 Hz, 1H) 7.46 (d,J=2.27 Hz, 1H) 7.14 (dd, J=8.97, 2.40 Hz, 1H) 6.76 (d, J=3.79 Hz, 1H)6.68 (s, 1H) 4.62 (d, J=6.57 Hz, 1H) 4.12 (d, J=2.27 Hz, 1H) 4.08 (d,J=1.52 Hz, 1H) 1.44 (d, J=6.57 Hz, 3H) 1.34 (s, 9H).

102-A-2:(+)-5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

R_(t)=6.54 min; MS (ESI) m/z 433.0 (M+1); 1H NMR (400 MHz, DMSO-d₆) δppm 8.54 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.46(d, J=2.27 Hz, 1H) 7.14 (dd, J=8.97, 2.40 Hz, 1H) 6.76 (d, J=3.79 Hz,1H) 6.68 (s, 1H) 4.62 (q, J=6.65 Hz, 1H) 4.12 (d, J=2.02 Hz, 1H) 4.08(d, J=1.52 Hz, 1H) 1.44 (d, J=6.57 Hz, 3H) 1.34 (s, 9H)

EXAMPLE 103 103-A.N-(3-(isopropylcarbamoyl)-5-(trifluoromethyl)phenyl)-5-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide

To a solution of4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-a]pyrimidine-7-carboxylicacid tert-butyl ester (0.16 g, 0.437 mmol) in 4 mL of THF at 0° C., NaH(0.105 g, 2.62 mmol) is added. After stirring for 45 min a solution ofphenyl 3-(isopropylcarbamoyl)-5-(trifluoromethyl)phenylcarbamate,Example 13-B, (0.224 g, 0.611 mmol) in 2 mL of THF and 1 mL of DMF isadded dropwise. The resulting mixture is stirred for 4 h before beingpartitioned between EtOAc and cold H₂O. The aq layer is extractedfurther with EtOAc and the combined organic layers are washed withsaturated aqueous NaHCO₃, brine and dried over Na₂SO₄. Followingconcentration the residue is separated by FCC (heptane/EtOAc). Theresulting product (0.23 g, 0.360 mmol) is then treated with 70 mL of 50%TFA in DCM at rt for 1 h. After concentration the residue is separatedby semi-prep HPLC (10-100% CAN/H₂O with 0.1% NH₄OH) to provide the titlecompound. MS (ESI) m/z 539.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.49 (br. S., 1H), 8.54 (d, J=7.8 Hz, 1H), 8.38-8.46 (m, 2H), 8.25-8.32(m, 2H), 8.15 (d, J=3.8 Hz, 1H), 7.98 (s, 1H), 7.46 (d, J=2.3 Hz, 1H),7.13 (dd, J=9.0, 2.4 Hz, 1H), 4.07-4.21 (m, J=13.9, 6.9, 6.7, 6.7 Hz,2H), 3.85 (s, 2H), 3.07 (t, J=5.8 Hz, 2H), 2.75 (t, J=5.7 Hz, 2H), 1.20(d, J=6.6 Hz, 6H).

The following compounds are prepared with similar method.

103-B.N-(3-(methylcarbamoyl)-5-(trifluoromethyl)phenyl)-5-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide

MS (ESI) m/z 511.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (br. S.,1H), 8.73 (q, J=4.0 Hz, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 8.24-8.32 (m,2H), 8.14 (d, J=3.8 Hz, 1H), 7.95 (s, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.13(dd, J=9.0, 2.4 Hz, 1H), 6.80 (d, J=3.5 Hz, 1H), 3.82 (s, 2H), 3.03 (t,J=5.8 Hz, 2H), 2.83 (d, J=4.3 Hz, 3H), 2.72 (t, J=5.6 Hz, 2H).

103-C.(±)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-isopropylcarbamoyl-5-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 533.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.49 (br. S.,1H), 8.53 (d, J=7.6 Hz, 1H), 8.39-8.44 (m, 2H), 8.25-8.33 (m, 2H), 8.14(d, J=3.8 Hz, 1H), 7.97 (s, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.12 (dd,J=9.0, 2.4 Hz, 1H), 6.79 (d, J=3.5 Hz, 1H), 4.06-4.21 (m, 1H), 3.81-3.97(m, 2 H), 2.91-3.03 (m, 1H), 2.85 (dd, J=16.9, 3.5 Hz, 1H), 2.29-2.39(m, 1H), 1.17-1.24 (m, 9H).

103-D.(±)-5-(6-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-methylcarbamoyl-5-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 525.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.49 (br. S.,1H), 8.70-8.77 (m, 1H), 8.42-8.47 (m, 1H), 8.44 (br. S., 1H), 8.40 (s,1H), 8.30 (d, J=9.1 Hz, 1H), 8.25-8.28 (m, 1H), 8.14 (d, J=3.8 Hz, 1H),7.93 (br. S., 1H), 7.45 (d, J=2.3 Hz, 1H), 7.12 (dd, J=8.8, 2.3 Hz, 1H),6.79 (d, J=3.8 Hz, 1H), 3.80-3.95 (m, 2H), 2.90-3.03 (m, 1H), 2.80-2.89(m, 4H), 2.34 (dd, J=16.3, 10.5 Hz, 1H), 1.22 (d, J=6.3 Hz, 3H).

EXAMPLE 104 104-A. Acetic acid4-[4-fluoro-2-methyl-1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-2-ylmethylester

DBU (5.48 mL, 36.3 mmol) is added dropwise to a suspension of4-fluoro-2-methyl-1H-indol-5-ol (5.00 g, 30.3 mmol) and2,4-dichloropyrimidine (4.60 g, 30.9 mmol) in CH₃CN (60 mL) at 0° C. Theresulting mixture is warmed to and stirred at 23° C. for 15 h. Thereaction mixture is concentrated and the residue is partitioned between1:1 EtOAc—CH₂Cl₂ (300 mL) and water (150 mL). The aqueous layer isextracted with EtOAc (2×100 mL). The combined organic layers are washedwith brine (100 mL), dried (Na₂SO₄), and concentrated. The residue ispurified by silica gel chromatography (0-100% EtOAc/heptane) to provide5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole.

1,2-Dibromoethane (425 μL, 5.0 mmol) is added to a suspension of zincpowder (2.83 g, 43.2 mmol) in dry DMF (8 mL). The reaction mixture isheated at 60° C. for 10 min, then cooled to room temperature. TMSCl (500μL, 4.0 mmol) is added (caution: exothermic!) and the resulting mixtureis sonicated for 30 min. Zinc powder is allowed to settle and thesupernatant is removed by syringe. DMF (8 mL) is added, followed bybromomethyl acetate (2.12 mL, 21.61 mmol). The mixture is stirred at 23°C. for 2.5 h. Zinc is allowed to settle and the solution ofacetoxymethylzinc bromide is then transferred to a solution of5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole (2.00 g, 7.20mmol), palladium acetate (0.081 g, 0.360 mmol), and S-phos (0.355 g,0.864 mmol) in DMF (10 mL) at 23° C. The resulting mixture is stirred at23° C. for 15 h. Saturated aqueous NH₄Cl (100 mL) is added and themixture is then partitioned between EtOAc (150 mL) and water (150 mL).The aqueous layer is extracted with EtOAc (2×100 mL). The combinedorganic layers are washed with brine (60 mL), dried (Na₂SO₄), andconcentrated. The residue is purified by silica gel chromatography(0-100% EtOAc/heptane) to give(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate.

LHMDS (1.0 M in THF, 7.68 mL, 7.68 mmol) is added over 1 min to asolution of (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methylacetate (1.21 g, 3.84 mmol) and 1-isocyanato-3-(trifluoromethyl)benzene(0.70 mL, 5.08 mmol) in THF (40 mL) at −78° C. for 40 min. Saturatedaqueous NH₄Cl (100 mL) and water (20 mL) are added and the mixture isextracted with EtOAc (3×60 mL). The combined organic layers are washedwith brine (30 mL), dried (Na₂SO₄), and concentrated. The residue ispurified by silica gel chromatography (0-100% EtOAc/heptane) to giveacetic acid4-[4-fluoro-2-methyl-1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-2-ylmethylester. MS (ESI) m/z 503.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.99(s, 1H) 8.68 (d, J=5.81 Hz, 1H) 8.12 (s, 1H) 7.92 (d, J=7.83 Hz, 1H)7.66 (t, J=8.08 Hz, 1H) 7.51-7.55 (m, 2H) 7.11-7.18 (m, 2H) 6.64 (s, 1H)5.02 (s, 2H) 2.59 (s, 3H) 1.88 (s, 3H).

104-B.4-Fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Potassium carbonate (289 mg, 2.09 mmol) is added to a solution of aceticacid4-[4-fluoro-2-methyl-1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-2-ylmethylester (1.05 g, 2.09 mmol) in MeOH (40 mL) at 23° C. The resultingmixture is stirred at 23° C. for 1 h. Saturated aqueous NH₄Cl (50 mL)and water (20 mL) are added and the mixture is extracted with EtOAc(3×50 mL). The organic layers are combined, washed with brine (30 mL),dried (Na₂SO₄), and concentrated. The residue is purified by silica gelchromatography (10-100% EtOAc/heptane) to provide4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 461.0 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.02 (s, 1H) 8.69 (d, J=5.56 Hz, 1H) 8.12 (s,1H) 7.91 (s, 1H) 7.66 (t, J=7.96 Hz, 1H) 7.52 (t, J=8.34 Hz, 2H) 7.17(dd, J=8.84, 7.83 Hz, 1H) 7.05 (d, J=5.56 Hz, 1H) 6.63 (s, 1H) 5.14 (t,J=6.19 Hz, 1H) 4.38 (d, J=6.32 Hz, 2H) 2.59 (s, 3H).

EXAMPLE 105 105-A.4-Fluoro-5-{2-[(2-hydroxy-ethylamino)-methyl]-pyrimidin-4-yloxy}-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Methanesulfonyl chloride (0.046 mL, 0.586 mmol) is added to a solutionof4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (180 mg, 0.391 mmol) and Et₃N(0.109 mL, 0.782 mmol) in CH₂Cl₂ (5 mL) at 0° C. After 10 min,ethanolamine (0.236 mL, 3.91 mmol) is added and the resulting mixture iswarmed to and stirred at 23° C. for 4 h. MeOH (2 mL) is added and thereaction is stirred for another 15 h. The reaction mixture ispartitioned between EtOAc (40 mL) and water (40 mL). The aqueous layeris extracted with EtOAc (2×40 mL). The combined organic layers arewashed with brine (30 mL), dried (Na₂SO₄), and concentrated. The residueis purified by silica gel chromatography (0-10% MeOH/CH₂Cl₂) to give4-fluoro-5-{2-[(2-hydroxy-ethylamino)-methyl]-pyrimidin-4-yloxy}-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 504.2 (M+1); ¹H NMR(400 MHz, MeOD) δ ppm 8.60 (d, J=5.81 Hz, 1H) 8.07 (s, 1H) 7.86 (s, 1H)7.57-7.62 (m, 1H) 7.46-7.51 (m, 2H) 7.09 (dd, J=8.84, 7.33 Hz, 1H) 6.98(d, J=5.81 Hz, 1H) 6.54 (s, 1H) 3.82 (s, 2H) 3.55-3.58 (m, 2H) 2.65-2.71(m, 2H) 2.62 (s, 3H).

The following compounds are prepared with similar method.

105-B.4-Fluoro-2-methyl-5-(2-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 474.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.67 (d, J=5.81Hz, 1H) 8.08 (s, 1H) 7.87 (d, J=8.34 Hz, 1H) 7.58-7.62 (m, 1H) 7.47-7.53(m, 2H) 7.05-7.11 (m, 2H) 6.53 (s, 1H) 4.09 (s, 2H) 2.63 (s, 3H) 2.62(s, 3H).

EXAMPLE 106 106-A.4-Fluoro-5-(2-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Methanesulfonyl chloride (0.046 mL, 0.586 mmol) is added to a solutionof4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide (180 mg, 0.391 mmol) and Et₃N(0.109 mL, 0.782 mmol) in CH₂Cl₂ (5 mL) at 0° C. After 10 min, methanolis added, followed by sodium methanesulfinate (798 mg, 7.82 mmol). Theresulting mixture is warmed to and stirred at 23° C. for 14 h. Themixture is concentrated and the residue is taken up in DMF (5 mL). Theresulting mixture is stirred at 23° C. for 24 h, then partitionedbetween EtOAc (40 mL) and water (40 mL). The aqueous layer is extractedwith EtOAc (2×40 mL). The combined organic layers are washed with brine(20 mL), dried (Na₂SO₄), and concentrated. The residue is purified bysilica gel chromatography (0-100% EtOAc/heptane) to give4-fluoro-5-(2-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 474.0 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.98 (s, 1H) 8.76 (d, J=5.81 Hz, 1H) 8.12 (s,1H) 7.91 (d, J=8.34 Hz, 1H) 7.64-7.69 (m, 1H) 7.53 (d, J=8.84 Hz, 2H)7.18-7.25 (m, 2H) 6.63 (s, 1H) 4.55 (s, 2H) 2.97 (s, 3H) 2.59 (s, 3H)

EXAMPLE 107 107-A. Tert-butyl4-(1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of tert-butyl4-O-(3-((tert-butyldimethylsilyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-a]pyrimidine-7(8H)-carboxylate(0.252 g, 0.361 mmol) in 6 mL of THF and 14 mL of water, 26 mL of aceticacid is added. The mixture is heated to 32° C. for 5 h at which pointthe reaction is diluted with EtOAc, washed with water/pyridine,saturated sodium bicarbonate, brine and dried over sodium sulfate,concentrated to give the title compound. MS (ESI) m/z 584.2 (M+1).

107-B. tert-Butyl4-(1-(3-((methylsulfonyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of tert-butyl4-(1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(0.211 g, 0.361 mmol) in 6 mL of DCM with DIEA (0.19 mL, 1.08 mmol) at0° C., methanesulfonyl chloride (0.037 mL, 0.469 mmol) is added and thereaction stirred for 3 h. At that point the reaction is diluted withEtOAc, washed with saturated sodium bicarbonate, brine and the organiclayer is dried over sodium sulfate. Concentration provides a mixture ofthe title compound and tert-butyl4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-a]pyrimidine-7(8H)-carboxylate(3:7), which is carried on to next step.

107-C.N-(3-((isopropylamino)methyl)-5-(trifluoromethyl)phenyl)-5-(5,6,7,8-tetrahydropyrido[3,4-c]pyrimidin-4-yloxy)-1H-indole-1-carboxamide

To a solution of the above mixture (0.15 g, 0.227 mmol) in 3 mL of DCM,isopropyl amine (0.06 mL, 0.680 mmol) is added followed by sodium iodide(0.1 g, 0.68 mmol). After 45 min, LC-MS shows that tert-butyl4-(1-(3-((methylsulfonyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylateis converted to desired product and the tert-butyl4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylateleft over. To the reaction 3 mL (0.227 mmol) of isopropyl amine is addedfollowed by NaI (0.1 g, 0.68 mmol) and the mixture is heated to 45° C.for 2 h. The solvent is then removed and the residue diluted with EtOAc,washed with H₂O, brine and the organic layer dried over Na₂SO₄.Following concentration the residue is separated by FCC (25-100%EtOAc/heptane). This product is then treated with 60 mL of 50% TFA/DCMat rt for 1.5 h. After concentration the residue is separated bysemi-prep HPLC (C-18; 10-100% I/H₂O with 0.1% NH₄OH) to provide thetitle compound. MS (ESI) m/z 525.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δppm 10.33 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.13 (d, J=3.8Hz, 1H), 7.95 (d, J=15.2 Hz, 2 H), 7.38-7.52 (m, 2H), 7.11 (dd, J=9.0,2.4 Hz, 1H), 6.78 (d, J=3.8 Hz, 1H), 3.81 (d, J=7.6 Hz, 4H), 3.03 (t,J=5.8 Hz, 2H), 2.68-2.79 (m, 3H), 1.03 (d, J=6.1 Hz, 6H).

EXAMPLE 108 108-A. 5-(2-Azidomethyl-pyridin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

A mixture of methanesulfonic acid4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]pyridine-2-ylmethylester (505 mg, 1.03 mmol) and sodium azide (201 mg, 3.12 mmol) in DMSO(5 mL) is heated at 80° C. for 2 h. The mixture is then diluted with DCM(100 mL) and water. The organic layer is washed further with brine andthen dried over anhydrous Na₂SO₄. Following concentration the residue isseparated via FCC (20-90% EtOAc/heptane) to give the title compound. MS(ESI) m/z 453.1 (M+1).

108-B. 5-(2-Aminomethyl-pyridin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

5-(2-Azidomethyl-pyridin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide (165 mg, 0.36 mmol) is dissolved in THF(5 mL) at 0° C. and lithium aluminum hydride (0.55 mL, 0.55 mmol, 1.0MTHF solution) is added. After 2 h, the mixture is quenched with waterbefore extraction with EtOAc. The organic layer is washed with saturatedaqueous NH₄Cl and then dried over anhydrous Na₂SO₄. Followingconcentration the residue is separated via semi-prep HPLC (C18; 10-100%I/H₂O with 0.1% NH₄OH) to give the title compound. MS (ESI) m/z 427.1(M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.29-8.39 (m, 2H), 8.15 (d, J=3.8Hz, 1H), 8.09 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H),7.50 (d, J=7.6 Hz, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.12 (dd, J=8.8, 2.5 Hz,1H), 7.00 (s, 1H), 6.81 (d, J=3.3 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 3.76(s, 2H).

EXAMPLE 109 109-A.4-[1-(3-Cyano-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester, Example 31-F (140 mg, 0.38 mmol) is dissolved inTHF (5 mL) and NaH (31 mg, 0.76 mmol, 60% in mineral oil) is addedfollowed by (3-cyano-5-trifluoromethyl-phenyl)-carbamic acid phenylester (428 mg, 1.15 mmol). After 24 h, the reaction is concentrated andthen partitioned between DCM and water. The crude residue is purifiedvia FCC (5-90% EtOAc/heptane) to give the title compound. MS (ESI) m/z579.2 (M+1).

109-D.5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-cyano-5-trifluoromethyl-phenyl)-amide

A solution of4-[1-(3-cyano-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester (132 mg, 0.28 mmol) in DCM (2 mL) and TFA (2 mL)is stirred at room temperature for 2 h. The reaction is concentrated invacuo and purified via semi-prep HPLC (C18; 10-100% I/H₂O with 0.1%NH₄OH) to give the title compound. MS (ESI) m/z 479.0 (M+1); ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.38-8.42 (m, 2H), 8.35 (s, 1H), 8.28 (d, J=8.8 Hz,1H), 8.07-8.12 (m, 2H), 7.47 (d, J=2.3 Hz, 1H), 7.14 (dd, J=8.8, 2.3 Hz,1H), 6.83 (d, J=3.3 Hz, 1H), 3.85 (s, 2H), 3.06 (t, J=5.8 Hz, 2H), 2.74(t, J=5.7 Hz, 2H).

The following compounds are prepared with similar method.

109-E.5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-methoxy-5-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 484.3 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.33 (br. S.,1H), 8.40 (s, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.10 (d, J=3.5 Hz, 1H), 7.60(s, 1H), 7.45 (s, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.02 (s, 1H), 6.79 (d,J=3.5 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 2H), 3.03 (t, J=5.8 Hz, 2H),2.67-2.76 (m, 2H).

EXAMPLE 110 110-A.5-{6-[(4-Bromo-butyrylamino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid (4-fluoro-3-trifluoromethyl-phenyl)-amide

5-(6-Aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4-fluoro-3-trifluoromethyl-phenyl)-amide (52.5 mg, 0.117 mmol) isdissolved in DCM (5 mL) at 0° C. DIEA (0.025 mL, 0.143 mmol) is addedfollowed by 4-bromo-butyryl chloride (0.020 mL, 0.172 mmol). Thereaction is stirred for 30 min before being diluted with ethyl acetateand washed with water. The organic layer is removed, dried, andconcentrated to provide the title compound. MS (ESI) m/z 595.6 (M+1).

110-B.5-[6-(2-Oxo-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (4-fluoro-3-trifluoromethyl-phenyl)-amide

5-{6-[(4-Bromo-butyrylamino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid (4-fluoro-3-trifluoromethyl-phenyl)-amide (0.353 g, 0.595 mmol) isdissolved in 10 mL THF and cooled to 0° C. Sodium hydride (63 mg, 1.5mmol, 60% in mineral oil) is added and the reaction is allowed to warmto room temperature overnight. The reaction is quenched with water anddiluted with ethyl acetate. The organic layer is removed, dried, andconcentrated and the residue is separated via semi-prep HPLC (C18;20-100% I/H₂O with 0.1% TFA) to provide the title compound. MS (ESI) m/z514.9 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.40 (s, 1H), 8.68 (d,J=1.01 Hz, 1H), 8.28 (d, J=9.09 Hz, 1H), 8.09-8.12 (m, 2H), 7.99-8.03(m, 1H), 7.57 (t, J=9.85 Hz, 1H), 7.49 (d, J=2.27 Hz, 1H), 7.15 (dd,J=8.97, 2.40 Hz, 1H), 6.94 (d, J=1.01 Hz, 1H), 6.81 (d, J=3.79 Hz, 1H),4.45 (s, 2H), 3.42 (t, J=6.95 Hz, 2H), 2.29-2.34 (m, 3H), 2.00 (t,J=7.58 Hz, 2H).

EXAMPLE 111 111-A.5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (2-methyl-benzofuran-5-yl)-amide

tert-Butyl4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate(152.2 mg, 0.432 mmol) is suspended in THF (5 mL), flushed with nitrogenand cooled to 0° C. NaH (33 mg, 0.825 mmol, 60% in mineral oil) is addedand mixture is stirred for 10 minutes. Phenyl2-methylbenzofuran-5-ylcarbamate (280 mg, 1.048 mmol) is added neat andthe reaction is allowed to stir to room temperature overnight. Thereaction is cooled in an ice bath and quenched with a saturated solutionof ammonium chloride (100 mL). The solution is then diluted with ethylacetate and the product is extracted (2×100 mL ethyl acetate). Theorganic layers are combined, dried and concentrated to a brown oil thatis dissolved in 10 mL of DCM and cooled in an ice bath upon which 10 mLof TFA is added. The TFA is removed and ethyl acetate is added to theresidue and ammonium hydroxide is added to quench the remaining TFA. Thesolution is concentrated and dissolved in DMSO and is purified viasemi-prep HPLC (C18; 20-100% I/H₂O with 0.1% TFA) to give5-(6,7-dihydro-5H-pyrrolo[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylicacid (2-methyl-benzofuran-5-yl)-amide. MS (ESI) m/z 426.0 (M+1); ¹H NMR(400 MHz, MeOD) δ ppm 8.53 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.15-8.20 (m,1H) 7.88-7.92 (m, 1H) 7.58 (ddd, J=6.13, 3.98, 2.27 Hz, 1H) 7.39-7.46(m, 2H) 7.12 (dd, J=9.09, 2.02 Hz, 1H) 6.74 (d, J=3.79 Hz, 1H) 6.46 (s,1H) 4.19 (d, J=9.35 Hz, 4H) 2.45 (s, 3H).

The following compounds are prepared with similar method.

111-B.5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (1-methyl-1H-indol-4-yl)-amide

MS (ESI) m/z 425.0 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm 8.54 (s, 1H) 8.30(d, J=9.09 Hz, 1H) 8.00 (d, J=3.54 Hz, 1H) 7.44 (d, J=2.53 Hz, 1H)7.19-7.33 (m, 4H) 7.11 (dd, J=9.09, 2.27 Hz, 1H) 6.75 (d, J=3.79 Hz, 1H)6.55 (d, J=3.28 Hz, 1H) 4.19 (d, J=1.52 Hz, 4H) 3.84 (s, 3H).

EXAMPLE 112 112-A.[6-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl]-methyl-amine

Methanesulfonic acid6-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl ester (2.5g, 8.78 mmol) is stirred in DCM (40.0 mL) with 1 M methylamine in THF(4.39 mL, 8.78 mmol) at rt for 24 h. The reaction is diluted with H₂Oand EtOAc. The organic layer is washed with brine, dried over Na₂SO₄,filtered, and purified by FCC eluting with first 10-100% EtOAc inheptanes, then washing with 0-25% MeOH with NH₃ in EtOAc to provide thetitle compound. MS (ESI) m/z 287.2 (M+1); ¹H NMR (400 MHz, MeOD) δ ppm8.63 (d, J=1.01 Hz, 1H) 7.11 (d, J=8.59 Hz, 1H) 7.02 (s, 1H) 6.85 (dd,J=8.59, 7.33 Hz, 1H) 6.23 (s, 1H) 3.81 (s, 2H) 2.41 (s, 3H) 2.44 (s,3H).

112-B.[6-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl]-methyl-carbamicacid tert-butyl ester

To a solution of[6-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl]-methyl-amine(0.68 g, 2.37 mmol) in THF (20 mL) is added BOC₂O (0.551 ml, 2.37 mmol)and TEA (0.33 mL, 2.37 mmol). The mixture is stirred at rt for 18 hbefore saturated aqueous NaHCO₃, water, and 150 mL EtOAc are added. Theaqueous phase is extracted further with 50 mL EtOAc. The organic layersare combined, washed with brine, and dried over Na₂SO₄. Followingconcentration the residue is purified by FCC (0-5% MeOH in DCM) to givethe title compound. MS (ESI) m/z 385.1 (M+1).

112-C.{6-[1-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-4-fluoro-2-methyl-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-methyl-carbamicacid tert-butyl ester

To a solution of[6-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl]-methyl-carbamicacid tert-butyl ester (275 mg, 0.712 mmol) in THF (7 mL), NaH (85 mg,2.13 mmol) is added under nitrogen at 0° C. The resulting mixture isstirred for 2 h. Then (5-tert-butyl-isoxazol-3-yl)-carbamic acid phenylester (370 mg, 1.42 mmol) is added to this mixture. The resultingmixture is allowed to warm to rt and stir for 18 h. The mixture is thenquenched with saturated aqueous ammonium chloride. The aqueous phase isextracted with EtOAc (2×). The combined organic layers are washed withbrine, dried over anhydrous sodium sulphate, concentrated and purifiedby FCC (0-70% EtOAc/heptane) to provide the title compound. MS (ESI) m/z553.1 (M+1).

112-D.4-Fluoro-2-methyl-5-(6-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

To a solution of{6-[1-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-4-fluoro-2-methyl-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-methyl-carbamicacid tert-butyl ester (0.25 g, 0.452 mmol) in DCM (10 mL) is added TFA(1.5 mL). After 3 h the solvent is removed by rotary evaporation and theresidue is diluted with DCM and water. Concentrated NH₄OH is added toneutralize and the aqueous phase is extracted twice with DCM. Theorganic layers are washed with brine, dried over Na₂SO₄, andconcentrated to give the title compound. MS (ESI) m/z 453.1 (M+1); ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.64 (d, J=1.01 Hz, 1H) 7.52 (d, J=8.59 Hz,1H) 7.19 (s, 1H) 7.15 (dd, J=8.72, 7.71 Hz, 1H) 6.65 (s, 1H) 6.58 (s,1H) 3.76 (s, 2H) 2.56 (s, 3H) 2.33 (s, 3H) 1.34 (s, 9H).

EXAMPLE 1135-(7-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-methyl-cyclopropyl)-1H-pyrazol-3-yl]-amide

Prepared from Example 54-Q with similar method as described for Example63-A. MS (ESI) m/z 444.3 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.13(br. S., 1H), 10.56 (s, 1H), 8.42 (s, 1H), 8.29 (d, J=9.1 Hz, 1H), 8.16(d, J=3.5 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.09 (dd, J=9.0, 2.4 Hz, 1H),6.70 (d, J=3.5 Hz, 1H), 6.29 (s, 1H), 3.51 (s, 2H), 2.84 (t, J=5.7 Hz,2H), 2.66-2.76 (m, 2H), 2.40 (s, 3H), 1.41 (s, 3H), 0.89-0.97 (m, 2H),0.74-0.83 (m, 2H).

EXAMPLE 1145-(7-Ethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-methyl-cyclopropyl)-1H-pyrazol-3-yl]-amide

Prepared from Example 54-Q with similar method as Example 37-A. MS (ESI)m/z 458.4 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.13 (s, 1H), 10.55(s, 1H), 8.42 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.16 (d, J=3.5 Hz, 1H),7.42 (d, J=2.3 Hz, 1H), 7.09 (dd, J=8.8, 2.3 Hz, 1H), 6.70 (d, J=3.5 Hz,1H), 6.30 (d, J=1.8 Hz, 1H), 3.56 (s, 2H), 2.80-2.88 (m, 2H), 2.73-2.80(m, 2H), 2.58 (q, J=7.3 Hz, 2 H), 1.41 (s, 3H), 1.12 (t, J=7.2 Hz, 3H),0.89-0.96 (m, 2H), 0.75-0.81 (m, 2H).

EXAMPLE 115 115-A.(±)-5-[7-(2-Hydroxy-ethyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide

Methyl bromoacetate (0.15 mL, 1.58 mmol) is added to a solution of5-(6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide, Example 52-B, (0.370 g, 0.792mmol) and TEA (0.44 mL, 3.17 mmol) in ACN (10 mL). The solution isallowed to stir overnight. The solution is then concentrated and theresidue separated directly via FCC (30-100% EtOAc/heptane) to give{6-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-aceticacid methyl ester.

LiAlH₄ (0.46 mL, 1.0 M THF) is added to a solution of{6-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-aceticacid methyl ester (0.125 g, 0.232 mmol) in THF (5 mL). After 0.5 h theexcess LiAlH₄ is quenched by the addition of saturated aqueous NH₄Cl.Workup is done with saturated aqueous NH₄Cl and DCM (25 mL each). Theresidue is then separated via semi-prep HPLC to give5-[7-(2-hydroxy-ethyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-a]pyrimidin-4-yloxy]-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 512.3 (M+1); ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.42 (s, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.11 (d,J=3.5 Hz, 1H), 8.09 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.57-7.65 (m, 1H),7.41-7.46 (m, 2H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.72-6.78 (m, 1H), 4.47(t, J=5.4 Hz, 1H), 3.75 (s, 2H), 3.57 (q, J=6.1 Hz, 2H), 3.12-3.22 (m,1H), 2.88-3.00 (m, 1H), 2.54-2.76 (m, 3H), 1.10 (d, J=6.6 Hz, 3 H).

The following compounds are prepared with similar method.

115-B.5-[(S)-7-(2-Hydroxy-ethyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylicacid (5-cyclopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 475.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.21 (s, 1H)8.42 (s, 1H) 8.27 (d, J=8.84 Hz, 1H) 8.15 (d, J=3.79 Hz, 1H) 7.44 (d,J=2.27 Hz, 1H) 7.13 (dd, J=8.97, 2.40 Hz, 1H) 6.74 (d, J=3.79 Hz, 1H)6.65 (s, 1H) 4.47 (t, J=5.43 Hz, 1H) 3.74 (s, 2H) 3.57 (q, J=6.06 Hz,2H) 3.13-3.19 (m, 1H) 2.93 (dd, J=16.67, 5.05 Hz, 1H) 2.60-2.73 (m, 2H)2.56 (dd, J=17.31, 5.68 Hz, 1H) 2.17 (tt, J=8.49, 5.02 Hz, 1H) 1.05-1.11(m, 5H) 0.92-0.97 (m, 2H).

EXAMPLE 116 116-A. Diethyl-carbamic acid 1H-indol-5-yl ester

5-Hydroxy indole (4.4 g, 33.0 mmol) is placed in pyridine (31 mL) andTEA (5.8 mL, 41.6 mmol) is added. Diethylcarbamoyl chloride (7 mL, 55.2mmol) is added neat and the resulting solution is stirred at roomtemperature for 4 hours. The reaction is then quenched with ice waterand diluted with ethyl acetate. The layers are separated and the aqueouslayer is further extracted with EtOAc (2×250 mL) and the organic layersare combined, dried (sodium sulfate) and concentrated to an orange oilthat is absorbed onto silica and separated via FCC (0-50% ethylacetate:heptanes) to obtain the title compound. MS (ESI) m/z 233.28(M+1).

116-B. Diethyl-carbamic acid1-(tert-butyl-dimethyl-silanyl)-1H-indol-5-yl ester

Diethyl-carbamic acid 1H-indol-5-yl ester (5.72 g, 24.6 mmol) isdissolved in THF (200 mL) and cooled to 0° C. The flask is purged withnitrogen and then 60% NaH (1.1 g, 27.5 mmol) is added and the mixturestirred in aen ice bath for 30 minutes. At that point TBDMSCl (0.210 g,1.39 mmol) is added and the reaction is allowed to stir overnight (14hours). The reaction is quenched with a saturated solution of ammoniumchloride and the mixture is diluted with ethyl acetate and water. Theorganic layer is removed, dried (sodium sulfate) and concentrated toobtain the title compound as an oil that is used without furtherpurification. MS (ESI) m/z 347.21 (M+1).

116-C. Diethyl-carbamic acid1-(tert-butyl-dimethyl-silanyl)-4-chloro-1H-indol-5-yl ester

Diethyl-carbamic acid 1-(tert-butyl-dimethyl-silanyl)-1H-indol-5-ylester (9.26 g, 26.7 mmol) is dissolved in THF (250 mL), flushed withnitrogen and cooled to −78° C. TMEDA (5 mL, 33.1 mmol) is then addedfollowed by sec-butyllithium (24.8 mL, 34.7 mmol) and the reaction isstirred for 30 minutes. Hexachloroethane (12.73 g, 53.8 mmol) in 50 mLof THF is added over 10 minutes to the reaction. The reaction is allowedto warm to room temperature overnight (15 hours). The reaction is cooledusing an ice bath and a saturated ammonium chloride (aq) solution isadded (150 mL). The mixture is then extracted with ethyl acetate, dried(sodium sulfate) and concentrated to obtain the title compound as an oilthat is used without further purification. MS (ESI) m/z 381.1 (M+1).

116-D. 4-Chloro-1H-indol-5-ol

Diethyl-carbamic acid1-(tert-butyl-dimethyl-silanyl)-4-chloro-1H-indol-5-yl ester (12.2 g,31.9 mmol) is dissolved in diethyl ether (250 mL) and LAH (1.21 g, 31.9mmol) is added and heated at 40° C. for 5 hours. The reaction is cooledto room temperature, placed in an ice bath and quenched with 0.5 N NaOH(aq). The reaction is diluted with ethyl acetate and the organic layeris removed, dried (sodium sulfate) and concentrated and the crudeproduct is used without further purification. MS (ESI) m/z 282.19 (M+1).

1-(tert-Butyl-dimethyl-silanyl)-4-chloro-1H-indol-5-ol (5.35 g, 18.98mmol) is dissolved in THF (90 mL) and cooled to 0° C. TBAF (4.96 g,18.98 mmol) is added over 5 minutes to the brown solution. After 1 hourthe reaction is quenched with ammonium chloride. The reaction is dilutedwith ethyl acetate and washed with water and then brine. The organicphase is removed, dried (sodium sulfate) and concentrated. The mixtureis absorbed onto silica and purified via FCC (0-40% ethylacetate:heptanes) to obtain the title compound as a solid. MS (ESI) m/z168.15 (M+1).

116-E.4-(4-Chloro-1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

Prepared with similar method to that described in Example 44-B. MS (ESI)m/z 388.96 (M+2).

EXAMPLE 117 117-A. 4-Methyl-1H-indol-5-ol

5-Methoxy-4-methyl-1H-indole (10 g, 62.0 mmol) is dissolved in DCM (400mL) and cooled to 0° C. BBr₃ (155 mL, 155 mmol) is added dropwise over 1hour and the black mixture is allowed to warm to room temperatureovernight (17 hours). The reaction is poured over a mixture of ice andsodium bicarbonate (aq) solution and extracted with ethyl acetate (1.5L) and concentrated to a black oil. The oil is absorbed onto silica andseparated via FCC (0-50% ethyl acetate:heptanes) to obtain the titlecompound as a solid. MS (ESI) m/z 148.23 (M+1).

117-B.4-(4-Methyl-1H-indol-5-yloxy)-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

Prepared with similar method to that described in Example 44B. MS (ESI)m/z 367.01 (M+1).

117-C.(S)-6-Methyl-4-(4-methyl-1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid tert-butyl ester

Prepared with similar method to that described for Example 31-C. MS(ESI) m/z 395.2 (M+1).

EXAMPLE 118 118-A.4-Chloro-5,6,7,9-tetrahydro-pyrimido[4,5-c]azepine-8-carboxylic acidtert-butyl ester & 118-B.4-Chloro-5,7,8,9-tetrahydro-1,3,6-triaza-benzocycloheptene-6-carboxylicacid tert-butyl ester

A mixture of 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester4-ethyl ester & 4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester3-ethyl ester is prepared as described in J Med Chem 1986, 29, 224 andthen is converted, with similar method to that described in Example 47D,into a mixture of4-oxo-3,4,5,7,8,9-hexahydro-1,3,6-triaza-benzocycloheptene-6-carboxylicacid tert-butyl ester and4-oxo-3,4,5,6,7,9-hexahydro-pyrimido[4,5-c]azepine-8-carboxylic acidtert-butyl ester which is then converted to the title compounds withsimilar method to that described in Example 47F, and subsequentseparation of the isomers 118-A & 118-B by FCC (15-45% EtOAc/heptane. MS(ESI) m/z 284.0 (M+1) for each.

The following compounds are prepared with similar method.

118-C. 4-Chloro-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylicacid tert-butyl ester

MS (ESI) m/z 284.0 (M+1)

EXAMPLE 119

The following compounds are prepared with similar method to Example47-G.

119-A.4-(1H-Indol-5-yloxy)-5,6,7,9-tetrahydro-pyrido[2,3-c]azepine-8-carboxylicacid tert-butyl ester

MS (ESI) m/z 381.1 (M+1)

119-B.4-(1H-Indol-5-yloxy)-5,7,8,9-tetrahydro-1,3,6-triaza-benzocycloheptene-6-carboxylicacid tert-butyl ester

MS (ESI) m/z 381.1 (M+1)

119-C.4-(1H-Indol-5-yloxy)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylicacid tert-butyl ester

MS (ESI) m/z 381.0 (M+1)

EXAMPLE 120 120-A. 5,7-Dihydro-3H-thieno[3,4-d]pyrimidin-4-one

Commercially available 4-carbomethoxytetrahydro-3-thiophenone (5 g, 31.2mmol) is dissolved in EtOH (284 mL). Formamidine acetate (22 g, 211mmol) is then added followed by sodium ethoxide (45 mL, 121 mmol, 21%w/w) and the mixture is heated at 90° C. for 14 hours. Reaction iscooled to room temperature and concentrated to a residue which isabsorbed onto silica and separated via FCC (0-10% Methanol:CH₂Cl₂) togive the title compound as a solid. MS (ESI) m/z 155.14 (M+1).

120-B. 4-(1H-Indol-5-yloxy)-5,7-dihydro-thieno[3,4-d]pyrimidine

Prepared with similar method to that described for Example 31-C. MS(ESI) m/z 270.07 (M+1).

120-C.5-(5,7-Dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid(2-fluoro-3-trifluoromethyl-phenyl)-amide

Prepared with similar method to that described for Example 45-A. MS(ESI) m/z 475.4 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.27 (s, 1H)8.56 (s, 1H) 8.25 (d, J=9.09 Hz, 1H) 8.09 (d, J=3.79 Hz, 1H) 7.91-7.95(m, 1H) 7.68-7.72 (m, 1H) 7.47-7.51 (m, 2H) 7.17 (d, J=9.09 Hz, 1H) 6.82(d, J=3.79 Hz, 1H) 4.33 (d, J=1.77 Hz, 4H).

The following compounds are prepared with similar method.

120-D.5-(5,7-Dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid[5-(1 trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide

MS (ESI) m/z 488.9 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.44 (s, 1H)8.56 (s, 1H) 8.30 (d, J=9.09 Hz, 1H) 8.16 (d, J=3.79 Hz, 1H) 7.49 (d,J=2.53 Hz, 1H) 7.18 (d, J=8.84 Hz, 1H) 7.04 (s, 1H) 6.78 (d, J=3.79 Hz,1H) 4.33 (d, J=1.77 Hz, 4H) 1.57 (d, J=1.52 Hz, 2H) 1.57 (d, J=9.60 Hz,2H).

120-E.5-(5,7-Dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid[5-(1-methyl-cyclopropyl)-1H-pyrazol-3-yl]-amide

MS (ESI) m/z 433.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (s, 1H)8.30 (d, J=9.09 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.46 (d, J=2.78 Hz, 1H)7.13 (d, J=9.09 Hz, 1H) 6.72 (d, J=3.79 Hz, 1H) 6.28 (s, 1H) 4.33 (d,J=2.02 Hz, 4H) 1.41 (s, 3H) 0.93 (d, J=2.02 Hz, 2H) 0.78 (d, J=2.02 Hz,2H).

120-F.5-(5,7-Dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-isopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 422.12 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.27 (s, 1H)8.56 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.49 (d,J=2.53 Hz, 1H) 7.17 (dd, J=8.97, 2.40 Hz, 1H) 6.77 (d, J=3.79 Hz, 1H)6.70 (s, 1H) 4.33 (d, J=1.77 Hz, 4H) 3.11 (quin, J=6.82 Hz, 1H) 1.29 (d,J=6.82 Hz, 6H).

120-G.5-(5,7-Dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-cyclopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 420.11 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.23 (s, 1H)8.56 (s, 1H) 8.29 (d, J=8.84 Hz, 1H) 8.16 (d, J=3.79 Hz, 1H) 7.48 (d,J=2.27 Hz, 1H) 7.17 (dd, J=8.97, 2.40 Hz, 1H) 6.77 (d, J=3.54 Hz, 1H)6.65 (s, 1H) 4.33 (d, J=1.52 Hz, 4H) 2.14-2.21 (m, 1H) 1.06-1.11 (m, 2H)0.92-0.97 (m, 2H).

120-H.5-(5,7-Dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-tert-butyl-isoxazol-3-yl)-amide

MS (ESI) m/z 436.14 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.28 (s, 1H)8.56 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.49 (d,J=2.53 Hz, 1H) 7.17 (dd, J=8.97, 2.40 Hz, 1H) 6.77 (d, J=3.79 Hz, 1H)6.68 (s, 1H) 4.33 (d, J=1.52 Hz, 4H) 1.34 (s, 9H).

120-I.5-(5,7-Dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 457.09 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.39 (s, 1H)8.56 (s, 1H) 8.28 (d, J=8.84 Hz, 1H) 8.08-8.15 (m, 2H) 7.98 (d, J=8.34Hz, 1H) 7.61-7.69 (m, 1H) 7.47-7.54 (m, 2H) 7.17 (dd, J=8.97, 2.40 Hz,1H) 6.81 (d, J=3.54 Hz, 1H) 4.33 (d, J=2.53 Hz, 4H).

120-J.5-(5,7-Dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid[5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide

MS (ESI) m/z 434.12 (M+1). ¹H NMR, (400 MHz, DMSO-d₆) δ ppm 11.24 (s,1H) 8.56 (s, 1H) 8.30 (d, J=9.09 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.48(d, J=2.27 Hz, 1H) 7.17 (dd, J=8.97, 2.40 Hz, 1H) 6.77 (d, J=3.54 Hz,1H) 6.67 (s, 1H) 4.33 (d, J=1.26 Hz, 4H) 1.46 (s, 3H) 1.13-1.17 (m, 2H)0.91-0.96 (m, 2H).

EXAMPLE 121 121-A. 5-(6,6-Dioxo-6,7-dihydro-5H-6lambda*6*-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide

A stock solution of ammonium molybdate tetrahydrate (240 mg, 0.19 mmol)in 50% w/v aqueous peroxide (0.6 mL) is prepared at 0° C. and 0.13 mL ofthe stock solution is added to a solution of5-(5,7-dihydro-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid[5-(1 trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide (55 mg, 0.113mmol) in EtOH (8 mL) at 0° C. After stirring overnight the reaction isquenched with water and extracted with EtOAc. The title compound is theseparated using FCC eluting with DCM:MeOH 100:0 to 95:5. MS (ESI) m/z520.8 (M+1). NMR (400 MHz, DMSO-d₆) δ ppm 11.45 (s, 1H) 8.68 (s, 1H)8.31 (d, J=9.09 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.52 (d, J=2.27 Hz, 1H)7.20 (dd, J=8.84, 2.53 Hz, 1H) 7.04 (s, 1H) 6.79 (d, J=4.29 Hz, 1H) 4.72(d, J=12.88 Hz, 4H) 1.52-1.64 (m, 4H).

The following compounds are prepared with similar method.

121-B.5-(6,6-Dioxo-6,7-dihydro-5H-6lambda*6*-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (2-fluoro-3-trifluoromethyl-phenyl)-amide

MS (ESI) m/z 507.8 (M+1).

121-C.5-(6,6-Dioxo-6,7-dihydro-5H-6lambda*6*-thieno[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-methyl-cyclopropyl)-1H-pyrazol-3-yl]-amide

MS (ESI) m/z 465.9 (M+1).

EXAMPLE 122

The following compounds are prepared with similar method to thatdescribed for Example 16-A.

122-A. 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid[5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide

MS (ESI) m/z 406.1 (M+1)

122-B. 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-cyclopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 392.1 (M+1)

122-C. 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-isopropyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 393.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.22 (br. S.,1H) 10.59 (s, 1H) 8.65 (d, J=1.01 Hz, 1H) 8.32 (s, 1H) 8.18 (br. S., 1H)7.46 (d, J=2.02 Hz, 1H) 7.11-7.13 (m, 1H) 6.98 (s, 1H) 6.72 (d, J=3.28Hz, 1H) 6.34 (s, 1H) 5.58-5.61 (m, 1H) 4.51 (d, J=5.81 Hz, 2 H) 2.97 (d,J=6.82 Hz, 1H) 1.25 (d, J=7.07 Hz, 6H).

122-D.5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-4-methyl-indole-1-carboxylic acid(5-isopropyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 407.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.21 (s, 1H)10.57 (s, 1H) 8.62 (d, J=1.01 Hz, 1H) 8.15-8.17 (m, 2H) 7.05 (d, J=8.84Hz, 1H) 6.96 (s, 1H) 6.83 (d, J=3.28 Hz, 1H) 6.34 (s, 1H) 4.50-4.53 (m,2H) 2.94-2.97 (m, 1H) 2.24 (s, 3H) 1.25 (d, J=6.82 Hz, 6 H).

122-E. 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-isopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 394.05 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.28 (s, 1H)8.65 (d, J=1.01 Hz, 1H) 8.32 (d, J=8.84 Hz, 1H) 8.18 (d, J=3.54 Hz, 1H)7.49 (d, J=2.27 Hz, 1H) 7.16 (dd, J=8.97, 2.40 Hz, 1H) 6.99 (d, J=1.01Hz, 1H) 6.78 (d, J=3.79 Hz, 1H) 6.70 (s, 1H) 5.61 (t, J=5.81 Hz, 1H)4.52 (d, J=5.81 Hz, 2H) 3.08-3.15 (m, 1H) 1.29 (d, J=6.82 Hz, 6H).

122-F. 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid[5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide

MS (ESI) m/z 460.12 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.45 (s, 1H)8.65 (d, J=1.01 Hz, 1H) 8.32 (d, J=9.09 Hz, 1H) 8.18 (d, J=3.79 Hz, 1H)7.49 (d, J=2.27 Hz, 1H) 7.17 (dd, J=8.97, 2.40 Hz, 1H) 7.04 (s, 1H) 6.99(d, J=1.01 Hz, 1H) 6.79 (d, J=3.79 Hz, 1H) 5.59-5.63 (m, 1H) 4.51-4.54(m, 2H) 1.54-1.60 (m, 4H).

EXAMPLE 123

The following compounds are prepared with similar method to thatdescribed in Example 27-A.

123-A. 5-(6-Tetrazol-1-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide

MS (ESI) m/z 458.0 (M+1).

123-B. 5-(6-Tetrazol-2-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide

MS (ESI) m/z 458.9 (M+1)

123-C. 5-(6-Tetrazol-2-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-cyclopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 444.01 (M+1). NMR (400 MHz, DMSO-d₆) δ ppm 11.24 (s, 1H)9.04 (s, 1H) 8.67 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.17 (d, J=3.79 Hz,1H) 7.50 (d, J=2.53 Hz, 1H) 7.17 (dd, J=8.97, 2.40 Hz, 1H) 7.10 (s, 1H)6.77 (d, J=3.79 Hz, 1H) 6.65 (s, 1H) 6.13 (s, 2H) 2.14-2.21 (m, 1H)1.06-1.11 (m, 2H) 0.93-0.97 (m, 2H).

123-D. 5-(6-Tetrazol-2-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-isopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 446.99 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.29 (s, 1H)9.04 (s, 1H) 8.67 (d, J=1.01 Hz, 1H) 8.31 (d, J=9.09 Hz, 1H) 8.18 (d,J=3.79 Hz, 1H) 7.51 (d, J=2.27 Hz, 1H) 7.18 (dd, J=8.97, 2.40 Hz, 1H)7.11 (s, 1H) 6.78 (d, J=3.79 Hz, 1H) 6.69 (d, J=1.01 Hz, 1H) 6.13 (s,2H) 3.11 (t, J=6.95 Hz, 1H) 1.29 (d, 6H).

123-E. 5-(6-Tetrazol-1-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-isopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 446.98 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.29 (s, 1H)9.52 (s, 1H) 8.68 (d, J=1.01 Hz, 1H) 8.31 (d, J=8.84 Hz, 1H) 8.18 (d,J=3.79 Hz, 1H) 7.50 (d, J=2.53 Hz, 1H) 7.13-7.19 (m, 2H) 6.78 (d, J=3.79Hz, 1H) 6.69 (s, 1H) 5.89 (s, 2H) 3.11 (t, J=6.57 Hz, 1H) 1.29 (d,J=6.82 Hz, 6H).

123-F. 5-(6-Tetrazol-1-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-cyclopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 444.99 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.24 (s, 1H)9.52 (s, 1H) 8.68 (d, J=1.01 Hz, 1H) 8.31 (d, J=9.09 Hz, 1H) 8.17 (d,J=3.54 Hz, 1H) 7.49 (d, J=2.27 Hz, 1H) 7.13-7.18 (m, 2H) 6.77 (d, J=3.79Hz, 1H) 6.65 (s, 1H) 5.88 (s, 2H) 2.14-2.21 (m, 1H) 1.09 (dd, J=8.59,2.53 Hz, 2H) 0.95 (dd, J=4.93, 2.40 Hz, 2H).

EXAMPLE 124 124-A.1-Methyl-3-(1-Methyl-cyclopropyl)-1H-pyrazol-5-ylamine

A solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (1.0 g, 8.1mmol), methylhydrazine (0.56 g, 12.2 mmol) and MeOH (40 mL) is heated at80° C. for 16 h. The solution is then concentrated in vacuo and theresidue is suspended in 5 mL DCM and 20 mL heptane, filtered to giveproduct. MS (ESI) m/z 152.3 (M+1).

124-B. [2-Methyl-5-(1-methyl-cyclopropyl)-2H-pyrazol-3-yl]-carbamic acidphenyl ester

Prepared with similar method as described in Example 5-D. MS (ESI) m/z272.2 (M+1).

EXAMPLE 125 1-Methyl-5-(1-Methyl-cyclopropyl)-1H-pyrazol-3-ylamine

To a solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (1.0 g,8.1 mmol) in EtOH (10 mL) is added 4N HCl in Dioxane (10 mL). Themixture is stirred at room temperature for 16 hour. Concentrated underreduced pressure, the residue is dissolved in MeOH (40 mL) and treatedwith methylhydrazine (0.56 g, 12.2 mmol). The mixture is heated at 80°C. for 16 h. The solution is then concentrated in vacuo and the residueis purified by HPLC give product. MS (ESI) m/z 152.3 (M+1).

EXAMPLE 126 [1-Methyl-5-(1-methyl-cyclopropyl)-1H-pyrazol-3-yl]-carbamicacid phenyl ester

Prepared from Example 125 with similar method as described in Example5-D. MS (ESI) m/z 272.2 (M+1).

EXAMPLE 127 127-A. 3-(2,5-Dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole

To a solution of 1-methyl-1H-pyrazol-3-amine (9.5 g, 98 mmol) andacetonylacetone (11.2 g, 98 mmol) in toluene (150 mL), AcOH (1.5 mL) isadded, heated to reflux with a water separator until the formation ofwater ceased. Concentrated to dry. The residue is purified by flashcolumn to give product. MS (ESI) m/z 176.3 (M+1).

127-B. 5-(2,5-Dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazole-3-carboxylicacid dimethylamide

To a solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (2.0g, 11.4 mmol) in THF (100 mL) at −78° C., 2.5M nBuLi in Hexane (5.5 mL,13.7 mmol) is added. After stirring for 1.5 hour dimethylcarbamylchloride (1.26 mL, 13.7 mmol) is added. After 10 min the ice bath isremoved and the reaction allowed to reach room temperature and stir atroom temperature for 2 hour before being poured into water, separated,and the water layer extracted with DCM. The organic layers are combinedand concentrated. The residue is purified by FCC to give the titlecompound. MS (ESI) m/z 247.2 (M+1).

127-C. 5-Amino-2-methyl-2H-pyrazole-3-carboxylic acid dimethylamide

A solution of potassium hydroxide (1.1 g, 19.5 mmol) in water (30 mL)and ethanol (30 mL) is added to a slurry of hydroxylamine hydrochloride(2.7 g, 39 mmol) in ethanol (50 mL).5-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazole-3-carboxylic aciddimethylamide (1.6 g, 6.5 mmol) is added and the mixture is refluxed for48 hours. The contents of the flask are then concentrated under reducedpressure and the residue is suspended in DCM. The suspension is heatedto reflux and then cooled down to room temperature, filtered and thefiltrate is concentrated to give crude product. MS (ESI) m/z 169.3(M+1).

127-D. (5-Dimethylcarbamoyl-1-methyl-1H-pyrazol-3-yl)carbamic acidphenyl ester

Prepared with similar method as described in Example 5-D. MS (ESI) m/z289.1 (M+1).

127-E. (1-tert-Butyl-5-methyl-1H-pyrazol-3-yl)-carbamic acid phenylester

Prepared with similar method as described in Examples 127-A to 127-D,starting with 1-tert-butyl-1H-pyrazol-3-ylamine. In the alkylation stepiodomethane is used in place of dimethylcarbamyl chloride. MS (ESI) m/z274.3 (M+1).

EXAMPLE 128 128-A. 3-(2,5-Dimethyl-pyrrol-1-yl)-5-isopropyl-1H-pyrazole

Prepared with similar method as described in Example 127-A starting from5-Isopropyl-1H-pyrazol-3-ylamine. MS (ESI) m/z 204.3 (M+1).

128-B. 3-(2,5-Dimethyl-pyrrol-1-yl)-5-isopropyl-1-methyl-1H-pyrazole

To a solution of 3-(2,5-dimethyl-pyrrol-1-yl)-5-isopropyl-1H-pyrazole(7.7 g, 37.9 mmol) in THF (400 mL) that is purged with nitrogen is addedNaH (2.272 g, 56.8 mmol) at 0° C. The mixture is stirred for 10 min inthe ice bath then for 10 min at room temperature. Met (4.74 mL, 76 mmol)is added and the mixture is stirred at room temperature for 1 h. At thatpoint the reaction is diluted with DCM and treated with saturatedsolution of ammonium chloride (10 mL). The mixture is concentrated todryness and the residue is partitioned in water and DCM. The organiclayer is combined, dried over sodium sulfate, concentrated and absorbedonto silica to purify by FCC (0-30% EtOAC/Heptane) to give5-(2,5-Dimethyl-pyrrol-1-yl)-3-isopropyl-1-methyl-1H-pyrazole (2.4 g,29%) as the first peak and3-(2,5-Dimethyl-pyrrol-1-yl)-5-isopropyl-1-methyl-1H-pyrazole (5.24 g,63%) as the second peak. MS (ESI) m/z 218.3 (m+1).

128-C. 5-Isopropyl-1-methyl-1H-pyrazol-3-ylamine

Prepared with similar method as described in Example 127-C starting with3-(2,5-Dimethyl-pyrrol-1-yl)-5-isopropyl-1-methyl-1H-pyrazole. MS (ESI)m/z 140.3 (M+1).

128-D. (5-Isopropyl-1-methyl-1H-pyrazol-3-yl)-carbamic acid phenyl ester

Prepared with similar method as described in Example 5-D starting with5-Isopropyl-1-methyl-1H-pyrazol-3-ylamine. MS (ESI) m/z 260.2 (M+1).

The following compounds are prepared with similar method.

MS (ESI) Structure/Chemical Name m/z (M − 1) 128-E

286.2 128-F

326.2

EXAMPLE 129 129-A.5-Cyclopropyl-3-(2,5-dimethyl-pyrrol-1-yl)-1H-pyrazole

Prepared with similar method as described in Example 127-A starting from5-cyclopropyl-1H-pyrazol-3-ylamine. MS (ESI) m/z 202.4 (M+1).

129-B. 1,5-Dicyclopropyl-3-(2,5-dimethyl-pyrrol-1-yl)-1H-pyrazole

A suspension of copper (II) acetate (0.902 g, 4.97 mmol) and2,2′-bipyridine (0.776 g, 4.97 mmol) in DCE (20 mL) is stirred at 70° C.for 15 min, then transferred to a suspension of cyclopropyltrifluoroborate potassium salt (1.47 g, 9.94 mmol) and5-Cyclopropyl-3-(2,5-dimethyl-pyrrol-1-yl)-1H-pyrazole (1 g, 4.97 mmol),and sodium carbonate (1.053 g, 9.94 mmol) in DCE (40 mL). The resultingdark-green mixture is stirred at 70° C. for 24 h. The reaction mixtureis partitioned between EtOAc and 1N HCl. The aqueous layer is extractedwith EtOAc. The combined organic layers are washed with brine, dried(Na₂SO₄) and concentrated. The residue (1.64 g) is purified by ISCO(EtOAc-heptane 0-30%) to provide the desired product (1.25 g) as acolorless oil. MS (ESI) m/z 242.3 (M+1).

129-C. 1,5-Dicyclopropyl-1H-pyrazol-3-ylamine

Prepared with similar method as described in Example 127-C starting from1,5-Dicyclopropyl-3-(2,5-dimethyl-pyrrol-1-yl)-1H-pyrazole. MS (ESI) m/z164.4 (M+1).

129-D. (1,5-Dicyclopropyl-1H-pyrazol-3-yl)-carbamic acid phenyl ester

Prepared with similar method as described in Example 5-D starting with1,5-Dicyclopropyl-1H-pyrazol-3-ylamine. MS (ESI) m/z 284.2 (M+1).

EXAMPLE 130 130-A.2-[5-(2,5-Dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazol-3-yl]-1,1,1-trifluoro-propan-2-ol

To a solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (1.5g, 8.6 mmol) in THF (100 mL) at −78° C., 2.5M nBuLi in Hexane (4.1 mL,10.3 mmol) is added and stirred for 1.5 hours followed by the additionof trifluoro-acetic acid ethyl ester (1.5 g, 10.3 mmol). After 10 minthe ice bath is removed and the reaction is allowed to reach roomtemperature. Then the reaction is cooled down to −78° C. again andmethylmagnesium bromide (1.0 M solution in hexane, 8.6 mL) is added.After 5 min the ice bath is removed and the mixture is stirred at roomtemperature for 3 hour, poured into water, separated, and the waterlayer is extracted with DCM. The organic layers are combined andconcentrated. The residue is purified by FCC to give the title compound.MS (ESI) m/z 288.1 (M+1).

130-B.3-(2,5-Dimethyl-pyrrol-1-yl)-1-methyl-5-(2,2,2-trifluoro-1-methoxy-1-methyl-ethyl)-1H-pyrazole

To a solution of2-[5-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazol-3-yl]-1,1,1-trifluoro-propan-2-ol(0.5 g, 1.7 mmol) in THF (10 mL) at 0° C., sodium hydride (0.21 g, 60%,5.2 mmol) is added, and the mixture is stirred for 10 min followed bythe addition of methyl iodide (0.22 mL, 3.5 mmol). The ice bath isremoved and the reaction mixture is stirred at room temperature for 5hour, poured into water, separated, and the water layer is extractedwith DCM. The organic layers are combined and concentrated. The residueis purified by FCC to give the title compound. MS (ESI) m/z 302.0 (M+1).

130-C.1-Methyl-5-(2,2,2-trifluoro-1-methoxy-1-methyl-ethyl)-1H-pyrazol-3-ylamine

A solution of potassium hydroxide (280 mg, 5 mmol) in water (6 mL) andethanol (6 mL) is added to a slurry of hydroxylamine hydrochloride (700mg, 10 mmol) in ethanol (9 mL). Then3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-5-(2,2,2-trifluoro-1-methoxy-1-methyl-ethyl)-1H-pyrazole(500 mg, 1.7 mmol) is added and the mixture is refluxed for 24 hours. Atthis point the contents of the flask are concentrated under reducedpressure and the residue is partitioned in water and DCM and separated.The water layer is extracted with DCM and the organic layers arecombined and concentrated to give the crude title compound. MS (ESI) m/z224.2 (M+1).

130-D.[1-Methyl-5-(2,2,2-trifluoro-1-methoxy-1-methyl-ethyl)-1H-pyrazol-3-yl]-carbamic

Prepared with similar method as described in Example 5-D. MS (ESI) m/z344.0 (M+1).

EXAMPLE 131 131-A. 3-(5-Amino-2H-pyrazol-3-yl)-3-methyl-butan-1-ol

Prepared by similar method to that described above for Example 5-Bstarting from α,α-dimethyl-γ-butyrolactone. MS (ESI) m/z 170.1 (M+1).

131-B. 4,4-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-ylamine

To a solution of the above pyrazole (3.35 g, 19.8 mmol) in THF (100 mL)at rt is added thionyl chloride (7.22 mL, 99 mmol). Stirring iscontinued for 2 h before the mixture is added slowly to 200 mL of 28%NH₄OH and 100 g ice. The aqueous slurry is then extracted with DCM(2×200 mL) and the combined organic layers are dried (Na₂SO₄) filteredand concentrated. The residue is then separated via FCC (1-10% MeOH/DCM)to give the title compound. MS (ESI) m/z 152.1 (M+1).

131-C. (4,4-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-carbamicacid phenyl ester

To a solution of Example 131-B (1.43 g, 9.46 mmol) and DCM (50 mL) at 0°C. is added lutidine (3.30 mL, 28.4 mmol) followed by phenylchloroformate (1.31 mL, 10.4 mmol). The solution is left to stir at rtfor 4 h. At that point the solution is washed with 2 M HCl and then theorganic layer is dried (Na₂SO₄), filtered, and concentrated. The residueis then separated by FCC (30-100% EtOAc/heptane) to provide the titlecompound. MS (ESI) m/z 272.1 (M+1).

The following compounds are prepared with similar method.

131-D.(3-Chloro-4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-carbamicacid phenyl ester

Prepared from3-Chloro-4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-ylaminewhich is isolated as a side product in the preparation of Example 131-Babove. MS (ESI) m/z 306.0, 308.0 (M+1).

131-E. (5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-carbamic acid phenylester

MS (ESI) m/z 244.086.1 (M+1).

131-F.(4,4-Dimethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-2-yl)-carbamicacid phenyl ester

MS (ESI) m/z 286.1 (M+1).

EXAMPLE 132 132-A. (4-Chloro-5-cyclopropyl-isoxazol-3-yl)-carbamic acidphenyl ester

(5-Cyclopropyl-isoxazol-3-yl)-carbamic acid phenyl ester (0.25 g, 1.024mmol) is dissolved in AcOH (7.31 mL) and NCS (0.205 g, 1.53 mmol) isadded and the reaction is heated to 79° C. for 2 hours. The reaction iscooled to room temperature and diluted with water and ethyl acetate. Theorganic layer is washed with 500 mL of water to remove the acid. Theorganic layer is dried (sodium sulfate) and concentrated to an oil (352mg) to obtain the title compound that is used without furtherpurification. MS (ESI) m/z 279.00 (M+1).

The following are prepared with similar method.

132-B. (5-tert-Butyl-4-chloro-isoxazol-3-yl)-carbamic acid phenyl ester

MS (ESI) m/z 295.02 (M+1).

132-C. [4-Chloro-5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-carbamic acidphenyl ester

MS (ESI) m/z 293.01 (M+1).

EXAMPLE 133 133-A. (5-Cyclopropyl-4-methyl-isoxazol-3-yl)-carbamic acidphenyl ester

(5-Cyclopropyl-isoxazol-3-yl)-carbamic acid phenyl ester (0.368 g, 1.51mmol) is dissolved in THF (10 mL) and cooled to −78° C. and flushed withnitrogen. N-butyllithium (2.17 mL, 3.47 mmol) is then added. The mixtureis stirred in the dry ice/acetone bath for 30 minutes. Methyl iodide(0.10 mL, 1.66 mmol) is added neat and the reaction is stirred for 2hours at −78° C. The reaction is quenched (0° C.) with 20 mL of asaturated solution of ammonium chloride, diluted with ethyl acetate andthe organic layer is removed, dried (sodium sulfate) and concentrated toan oil that is purified via FCC (0-40% ethyl acetate:heptanes) to givethe title compound as an oil. MS (ESI) m/z 259.20 (M+1).

The following are prepared with similar method.

133-B. (5-tert-Butyl-4-methyl-isoxazol-3-yl)-carbamic acid phenyl ester

MS (ESI) m/z 275.24 (M+1)

133-C. [4-Methyl-5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-carbamic acidphenyl ester

MS (ESI) m/z 273.17 (M+1).

133-D. (5-tert-Butyl-4-methoxymethyl-isoxazol-3-yl)-carbamic acid phenylester

MS (ESI) m/z 305.00 (M+1).

EXAMPLE 134

The following compounds are prepared with similar methods to thosedescribed for Examples 54 and 56.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 134-A

(DMSO-d₆) δ ppm 8.36 (s, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 8.14 (d, J =3.8 Hz, 1 H), 7.40 (d, J = 2.5 Hz, 1 H), 7.08 (dd, J = 9.0, 2.4 Hz, 1H), 7.04 (s, 1 H), 6.74 (d, J = 3.5 Hz, 1 H), 3.96 (s, 2 H), 3.00- 3.12(m, 4 H), 1.70-1.81 (m, 2 H), 1.49-1.60 (m, 4 H) 499.1 134-B

(DMSO-d₆) δ ppm 8.35 (s, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 8.13 (d, J =3.8 Hz 1 H), 7.38 (d, J = 2.5 Hz, 1 H), 7.06 (dd, J = 9.0, 2.1 Hz, 1 H),6.70 (d, J = 2.8 Hz, 1 H), 6.64 (s, 1 H), 3.93 (s, 2 H), 2.96- 3.13 (m,4 H), 2.09-2.22 (m, 1 H), 1.68-1.82 (m, 2 H), 1.03-1.15 (m, 2 H),0.88-0.97 (m, 2 H) 431.1 134-C

(DMSO-d₆) δ ppm 8.37 (s, 1 H), 8.29 (d, J = 9.1 Hz, 1 H), 8.15 (d, J =3.5 Hz, 1 H), 7.40 (d, J = 2.3 Hz, 1 H), 7.09 (dd, J = 9.0, 2.4 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1 H), 6.68 (s, 1 H), 4.03 (s, 2 H), 3.02- 3.13(m, 4 H), 1.63-1.75 (m, 2 H), 1.34 (s, 9 H) 447.1 134-D

(DMSO-d₆) δ ppm 8.36 (s, 1 H) 8.28 (d, J = 8.84 Hz, 1 H) 8.15 (d, J =3.79 Hz, 1 H) 7.40 (d, J = 2.53 Hz, 1 H) 7.09 (dd, J = 8.97, 2.40 Hz, 1H) 6.74 (d, J = 3.54 Hz, 1 H) 6.68 (s, 1 H) 3.94 (s, 2 H) 3.01- 3.10 (m,4 H) 1.69-1.81 (m, 2 H) 1.34 (s, 9 H) 447.1 134-E

(DMSO-d₆) δ ppm 8.32-8.38 (m, 2 H) 8.12 (d, J = 3.79 Hz, 1 H) 7.37 (d, J= 2.27 Hz, 1 H) 7.06 (dd, J = 8.84, 2.27 Hz, 1 H) 7.03 (s, 1 H) 6.68 (d,J = 3.54 Hz, 1 H) 3.06 (t, J = 9.22 Hz, 4 H) 2.89- 2.98 (m, 4 H)1.49-1.57 (m, 4 H) 499.0 134-F

(DMSO-d₆) δ ppm 10.62 (s, 1 H) 8.37 (s, 1 H) 8.28 (d, J = 8.84 Hz, 1 H)8.14 (d, J = 3.79 Hz, 1 H) 7.37 (d, J = 2.27 Hz, 1 H) 7.06 (dd, J =8.97, 2.40 Hz, 1 H) 6.69 (d, J = 3.28 Hz, 1 H) 6.40 (s, 1 H) 4.02 (s, 2H) 3.96 (t, J = 6.19 Hz, 2 H) 3.02-3.11 (m, 4 H) 1.95-2.06 (m, 2 H)1.64-1.74 (m, 4 H) 1.30 (s, 6 H) 472.2 134-G

(DMSO-d₆) δ ppm 10.61 (br. S., 1 H) 8.37 (s, 1 H) 8.27 (d, J = 8.84 Hz,1 H) 8.13 (d, J = 3.79 Hz, 1 H) 7.38 (d, J = 2.53 Hz, 1 H) 7.06 (dd, J =8.84, 2.27 Hz, 1 H) 6.70 (d, J = 3.28 Hz, 1 H) 6.27 (s, 1 H) 4.09 (t, J= 6.95 Hz, 2 H) 4.04 (s, 2 H) 3.08 (ddd, J = 10.80, 5.68, 5.49 Hz, 4 H)2.31-2.36 (m, 2 H) 1.67-1.77 (m, 2 H) 1.32 (s, 6 H) 458.2 134-H

(DMSO-d₆) δ ppm 10.61 (s, 1 H) 8.35 (s, 1 H) 8.27 (d, J = 8.84 Hz, 1 H)8.13 (d, J = 3.79 Hz, 1 H) 7.38 (d, J = 2.53 Hz, 1 H) 7.06 (dd, J =8.97, 2.40 Hz, 1 H) 6.70 (d, J = 3.79 Hz, 1 H) 6.27 (s, 1 H) 4.09 (t, J= 6.82 Hz, 2 H) 3.94 (s, 2 H) 3.00-3.10 (m, 4 H) 2.34 (t, J = 6.95 Hz, 2H) 1.70-1.79 (m, 2 H) 1.32 (s, 6 H) 458.2 134-I

(DMSO-d₆) δ ppm 8.36 (s, 1 H) 8.28 (d, J = 8.84 Hz, 1 H) 8.14 (d, J =3.54 Hz, 1 H) 7.39 (d, J = 2.53 Hz, 1 H) 7.08 (dd, J = 8.97, 2.40 Hz, 1H) 6.71 (d, J = 3.54 Hz, 1 H) 6.64 (s, 1 H) 3.04 (dt, J = 10.04, 4.96Hz, 4 H) 2.85-2.93 (m, 4 H) 2.16 (tt, J = 8.37, 5.02 Hz, 1 H) 1.03-1.10(m, 2 H) 0.89-0.96 (m, 2 H) 431.1 134-J

(DMSO-d₆) δ ppm 10.63 (br. S., 1 H), 8.55 (s, 1 H), 8.28 (d, J = 9.1 Hz,1 H), 8 15 (d, J = 3.5 Hz, 1 H), 7.45 (d, J = 2.5 Hz, 1 H), 7.12 (dd, J= 8.8, 2.5 Hz, 1 H), 6.71 (d, J = 3.5 Hz, 1 H), 6.27 (s, 1 H), 4.05-4.13(m, 6 H), 2.34 (app t, J = 6.9 Hz, 2 H), 1.32 (s, 6 H) 430.1 134-K

(DMSO-d₆) δ ppm 10.62 (s, 1 H), 8.40 (s, 1 H), 8.27 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 3.81 Hz, 1 H), 7.41 (s, 1 H), 7.08 (dd, J = 9.0, 2.4Hz, 1 H), 6.70 (d, J = 3.5 Hz, 1 H), 6.27 (s, 1 H), 4.09 (app t, J = 6.9Hz, 2 H), 3.75-3.98 (m, 2 H), 2.89-3.05 (m, 1 H), 2.85 (dd, J = 16.8,3.4 Hz, 1 H), 2.24-2.40 (m, 3 H), 1.32 (s, 6 H), 1.21 (d, J = 6.3 Hz, 3H) 458.1 134-L

(DMSO-d₆) δ ppm 10.62 (s, 1 H) 8.37 (s, 1 H) 8.28 (d, J = 9.09 Hz, 1 H)8.15 (d, J = 3.79 Hz, 1 H) 7.38 (d, J = 2.27 Hz, 1 H) 7.06 (dd, J =8.84, 2.27 Hz, 1 H) 6.69 (d, J = 3.54 Hz, 1 H) 6.40 (s, 1 H) 3.93-4.01(m, 4 H) 3.03-3.13 (m, 4 H) 1.98-2.06 (m, 2 H) 1.73-1.81 (m, 2 H)1.64-1.70 (m, 2 H) 1.30 (s, 6 H) 472.2 134-M

(DMSO-d₆) δ ppm 10.64 (s, 1 H), 8.53 (s, 1 H), 8.31 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 3.8 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.10 (dd, J =9.0, 2.4 Hz, 1 H), 6.72 (d, J = 3.8 Hz, 1 H), 6.40 (s, 1 H), 4.18- 4.41(m, 2 H), 3.90-4.02 (m, 2 H), 3.44-3.64 (m, 1 H), 3.13 (dd, J = 17.6,4.2 Hz, 1 H), 2.66 (dd, J = 16.8, 10.7 Hz, 1 H), 1.94-2.08 (m, 2 H),1.60-1.75 (m, 2 H), 1.39 (d, J = 6.6 Hz, 3 H), 1.30 (s, 6 H) 472.2 134-N

(DMSO-d₆) δ ppm 10.59 (s, 1 H), 8.40 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 3.8 Hz, 1 H), 7.41 (d, J = 2.3 Hz, 1 H), 7.08 (dd, J =8.8, 2.3 Hz, 1 H), 6.71 (d, J = 3.5 Hz, 1 H), 6.28 (s, 1 H), 4.04 (t, J= 7.2 Hz, 2 H), 3.76-3.94 (m, 2 H), 2.91-3.03 (m, 1 H), 2.78-2.92 (m, 3H), 2.54-2.62 (m, 1 H), 2.33 (dd, J = 16.7, 10.4 Hz, 1 H), 1.21 (d, J =6.3 Hz, 3 H) 430.0 134-O

(DMSO-d₆) δ ppm 8.39 (s, 1 H) 8.32 (d, J = 9.09 Hz, 1 H) 8.14 (d, J =3.79 Hz, 1 H) 7.39 (d, J = 2.53 Hz, 1 H) 7.08 (dd, J = 8.97, 2.40 Hz, 1H) 7.03 (s, 1 H) 6.73 (d, J = 3.54 Hz, 1 H) 4.07 (s, 2H) 3.10 (dt, J =17.75, 5.40 Hz, 4 H) 1.67-1.79 (m, 2 H) 1.48-1.60 (m, 4 H) 499.0 134-P

(DMSO-d₆) δ ppm 10.10 (br. S., 1 H), 8.39 (s, 1 H), 8.23 (d, J = 9.1 Hz,1 H), 8.04 (d, J = 3.8 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.10 (dd, J= 9.0, 2.4 Hz, 1 H), 6.77 (d, J = 3.8 Hz, 1 H), 4.18 (t, J = 7.1 Hz, 2H), 3.78-3.97 (m, 2 H), 2.90-3.04 (m, 1 H), 2.85 (dd, J = 16.8, 3.9 Hz,1 H), 2.35-2.43 (m, 2 H), 2.25- 2.35 (m, 1 H), 1.39 (s, 6 H), 1.21 (d, J= 6.3 Hz, 3 H) 492.1, 494.0 134-Q

(DMSO-d₆) δ ppm 8.37 (s, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 8.14 (d, J =3.8 Hz, 1 H), 7.39 (d, J = 2.5 Hz, 1 H), 7.09 (dd, J = 9.0, 2.4 Hz, 1H), 6.73 (d, J = 3.8 Hz, 1 H), 6.65 (s, 1 H), 4.04 (s, 2 H), 3.03-3.14(m, 4 H), 2.12-2.22 (m, 1 H), 1.67-1.76 (m, 2 H), 1.04-1.12 (m, 2 H),0.91-0.97 (m, 2 H) 431.1 134-R

(MeOD) δ ppm 8.53 (s, 1 H) 8.34 (d, J = 9.09 Hz, 1 H) 7.90 (d, J = 3.79Hz, 1 H) 7.42 (d, J = 2.53 Hz, 1 H) 7.12 (dd, J = 8.84, 2.27 Hz, 1 H)6.79 (s, 1 H) 6.72 (d, J = 3.54 Hz, 1 H) 4.20 (d, J = 8.08 Hz, 4 H) 3.86(s, 3 H) 3.19 (s, 3 H) 3.13 (s, 3 H) 447.0 134-S

(MeOD) δ ppm 8.37 (s, 1 H) 8.31 (d, J = 9.09 Hz, 1 H) 7.86 (d, J = 3.54Hz 1 H) 7.38 (d, J = 2.27 Hz, 1 H) 7.08 (dd, J = 8.97, 2.15 Hz, 1 H)6.70 (d, J = 3.03 Hz, 1 H) 6.32 (d, J = 1.26 Hz, 1 H) 4.00 (d, J = 5.05Hz, 2 H) 3.86 (s, 3 H) 3.12 (ddd, J = 3.35, 1.58, 1.39 Hz, 1 H) 3.00(ddd, J = 17.05, 2.02, 1.89 Hz, 1 H) 2.51 (s, 1 H) 1.38 (s, 3 H) 1.34(d, J = 6.32 Hz, 3 H) 0.89 (br. S., 2 H) 0.77-0.84 (m, 2 H) 458.0 134-T

(DMSO-d₆) δ ppm 8.40 (s, 1 H) 8.25 (d, J = 9.09 Hz, 1 H) 8.04 (d, J =3.54 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1 H) 7.10 (dd, J = 8.97, 2.40 Hz, 1H) 6.77 (d, J = 3.54 Hz, 1 H) 6.05 (s, 1 H) 3.83 (s, 2 H) 3.65 (s, 3 H)3.04 (t, J = 5.81 Hz, 2 H) 2.73 (t, J = 5.68 Hz, 2 H) 1.38 (s, 3 H)0.85- 0.88 (m, 2 H) 0.67-0.70 (m, 2 H) 444.0 134-U

(DMSO-d₆) δ ppm 8.37 (s, 1 H) 8.32 (d, J = 9.09 Hz, 1 H) 7.88 (d, J =3.79 Hz, 1 H) 7.39 (d, J = 1.77 Hz, 1 H) 7.09 (dd, J = 9.09, 2.27 Hz, 1H) 6.74 (s, 1 H) 6.71 (d, J = 3.79 Hz, 1 H) 3.93 = 3.98 (m, 5 H) 3.35(s, 3 H) 3.18 (t, J = 5.94 Hz, 2 H) 2.88 (t, J = 5.68 Hz, 2 H) 1.84 (s,3 H) 515.9 134-V

(MeOD) δ ppm 8.53 (s, 1 H) 8.31 (d, J = 9.09 Hz, 1 H) 7.87 (d, J = 3.79Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1 H)6.71 (d, J = 3.79 Hz, 1 H) 6.33 (s, 1 H) 4.19 (d, J = 6.57 Hz, 4 H) 3.86(s, 3 H) 1.38 (s, 3 H) 0.88- 0.91 (m, 2 H) 0.79-0.83 (m, 2 H) 430.0134-W

(DMSO-d₆) δ ppm 8.55 (s, 1 H) 8.30 (d, J = 9.09 Hz, 1 H) 8.17 (d, J =3.79 Hz, 1 H) 7.45 (d, J = 2.78 Hz, 1 H) 7.12 (dd, J = 9.09, 2.27 Hz, 1H) 6.75 (s, 1 H) 6.73 (d, J = 3.79 Hz, 1 H) 4.06-4.12 (m, 4 H) 3.91 (s,3 H) 3.17 (s, 3 H) 1.81 (s, 3 H) 501.9 134-X

(MeOD) δ ppm 8.36 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 7.85 (d, J = 3.79Hz, 1 H) 7.37 (d, J = 2.27 Hz, 1 H) 7.07 (dd, J = 8.84, 2.27 Hz, 1 H)6.69 (d, J = 3.79 Hz, 1 H) 6.32 (s, 1 H) 3.93 (s, 2 H) 3.85 (s, 3 H)3.16 (t, J = 5.94 Hz, 2 H) 2.86 (t, J = 5.81 Hz, 2 H) 1.37 (s, 3 H)0.87- 0.90 (m, 2 H) 0.78-0.81 (m, 2 H) 444.1 134-Y

(DMSO-d₆) 8.55 (s, 1 H) 8.26 (dd, J = 6.32, 2.53 Hz, 2 H) 7.33 (d, J =8.84 Hz, 1 H) 6.83 (d, J = 3.79 Hz, 1 H) 6.65 (s, 1 H) 4.21 (s, 2 H)4.12 (s, 2 H) 2.10- 2.25 (m, 1 H) 0.84-1.21 (m, 4 H) 437.11 134-Z

(DMSO-d₆) ppm 12.13 (br. S., 1 H) 10.56 (br. S., 1 H) 8.52 (s, 1 H)8.12- 8.17 (m, 2 H) 7.05 (d, J = 8.84 Hz, 1 H) 6.81 (d, J = 3.79 Hz, 1H) 6.29 (br. S., 1 H) 4.07-4.14 (m, 4 H) 2.22-2.25 (m, 3 H) 1.41 (s, 3H) 0.91-0.94 (m, 2 H) 0.76-0.79 (m, 2 H) 430.19 134-AA

(DMSO-d₆) ppm 8.55 (s, 1 H) 8.23- 8.32 (m, 2 H) 7.33 (d, J = 8.84 Hz, 1H) 6.83 (d, J = 3.54 Hz, 1 H) 6.67 (s, 1 H) 4.21 (s, 2 H) 4.12 (s, 2 H)1.34 (s, 9 H) 453.14 134-AB

(DMSO-d₆) ppm 8.52 (s, 1 H) 8.11- 8.16 (m, 2 H) 7.09 (d, J = 9.09 Hz, 1H) 6.88 (d, J = 3.79 Hz, 1 H) 6.69 (s, 1 H) 4.14 (s, 2 H) 4.08-4.10 (m,2 H) 3.11 (t, J = 6.57 Hz, 1 H) 2.24 (s, 3 H) 1.29 (d, J = 7.07 Hz, 6 H)419.18 134-AC

(DMSO-d₆) ppm 8.52 (s, 1 H) 8.10- 8.15 (m, 2 H) 7.09 (d, J = 8.84 Hz, 1H) 6.87 (d, J = 3.79 Hz, 1 H) 6.65 (s, 1 H) 4.14 (s, 2 H) 4.06-4.10 (m,2 H) 2.24 (s, 3 H) 2.17 (s, 1 H) 1.06-1.11 (m, 2 H) 0.92-0.96 (m, 2 H)417.16 134-AD

(DMSO-d₆) ppm 8.55 (s, 1 H) 8.27 (dd, J = 6.06, 2.27 Hz, 2 H) 7.33 (d, J= 9.09 Hz, 1 H) 6.83 (d, J = 3.79 Hz, 1 H) 6.69 (s, 1 H) 4.22 (s, 2 H)4.13 (s, 2 H) 3.11 (quin, J = 6.88 Hz, 1 H) 1.29 (d, J = 6.82 Hz, 6 H)439.12 134-AE

(DMSO-d₆) ppm 8.53 (s, 1 H) 8.11- 8.16 (m, 2 H) 7.10 (d, J = 9.09 Hz, 1H) 7.05 (s, 1 H) 6.89 (d, J = 3.79 Hz, 1 H) 4.17 (s, 2 H) 4.11 (s, 2 H)2.24 (s, 3 H) 1.53-1.60 (m, 4 H) 485.15 134-AF

(DMSO-d₆) ppm 8.37 (s, 1 H) 8.13 (dd, J = 6.32, 2.53 Hz, 2 H) 7.04-7.07(m, 2 H) 6.87 (d, J = 3.79 Hz, 1 H) 3.89 (d, J = 10.36 Hz, 2 H) 3.00(ddd, J = 10.11, 6.32, 4.04 Hz, 1 H) 2.90 (dd, J = 16.80, 3.41 Hz, 1 H)2.32-2.45 (m, 1 H) 2.22 (s, 3 H) 1.52-1.60 (m, 4 H) 1.23 (d, J = 6.32Hz, 3 H) 513.18 134-AG

(DMSO-d₆) ppm 8.36 (s, 1 H) 8.10- 8.14 (m, 2 H) 7.05 (d, J = 9.09 Hz, 1H) 6.86 (d, J = 3.79 Hz, 1 H) 6.65 (s, 1 H) 3.88 (d, J = 9.60 Hz, 2 H)2.94-3.02 (m, 1 H) 2.88 (dd, J = 16.93, 3.79 Hz, 1 H) 2.37 (dd, J =16.93, 10.61 Hz, 1 H) 2.14-2.23 (m, 4 H) 1.22 (d, J = 6.06 Hz, 3 H)1.06-1.11 (m, 2 H) 0.92-0.96 (m, 2 H) 445.19 134-AH

(DMSO-d₆) ppm 8.36 (s, 1 H) 8.09- 8.16 (m, 2 H) 7.05 (d, J = 8.84 Hz, 1H) 6.86 (d, J = 3.79 Hz, 1 H) 6.67 (s, 1 H) 3.80-3.96 (m, 2 H) 2.87 (s,1 H) 2.67 (t, J = 1.89 Hz, 1 H) 2.30-2.40 (m, 1 H) 2.22 (s, 3 H) 1.46(s, 3 H) 1.23 (d, J = 6.32 Hz, 3 H) 1.11-1.18 (m, 2 H) 0.90-0.97 (m, 2H) 459.21 134-AI

(DMSO-d₆) ppm 8.36 (s, 1 H) 8.09- 8.16 (m, 2 H) 7.05 (d, J = 8.84 Hz, 1H) 6.86 (d, J = 3.79 Hz, 1 H) 6.69 (s, 1 H) 3.81-3.95 (m, 2 H) 3.10 (d,J = 7.07 Hz, 1 H) 2.99 (br. S., 1 H) 2.89 (d, J = 14.65 Hz, 1 H)2.31-2.43 (m, 1 H) 2.22 (s, 3 H) 1.29 (d, J = 6.82 Hz, 6 H) 1.23 (d, J =6.32 Hz, 3 H) 447.21 134-AJ

(DMSO-d₆) ppm 8.55 (s, 1 H) 8.25 (d, J = 9.09 Hz, 1 H) 8.07 (d, J = 3.54Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J = 8.97, 2.40 Hz, 1 H)6.78 (d, J = 3.54 Hz, 1 H) 4.10 (d, J = 14.91 Hz, 4 H) 2.12-2.19 (m, 1H) 1.95 (s, 3 H) 0.94- 1.10 (m, 4 H) 417.03 134-AK

(DMSO-d₆) ppm 8.55 (s, 1 H) 8.24 (d, J = 8.84, 1 H) 8.23 (s, 1 H) 8.07(d, J = 3.79 Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.14 (dd, J = 8.97,2.40 Hz, 1 H) 6.79 (d, J = 3.79 Hz, 1 H) 4.11 (d, J = 15.16 Hz, 4 H)1.98 (s, 3 H) 1.38 (s, 9 H) 433.19 134-AL

(DMSO-d₆) ppm 8.58 (s, 1 H) 8.29 (d, J = 9.09 Hz, 1 H) 8.04 (d, J = 3.79Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.14 (dd, J = 8.97, 2.40 Hz, 1 H)6.77 (d, J = 3.54 Hz, 1 H) 4.15 (d, J = 13.89 Hz, 4 H) 2.17-2.24 (m, 1H) 1.07-1.20 (m, 4 H) 437.11 134-AM

(DMSO-d₆) ppm 8.55 (s, 1 H) 8.24 (d, J = 9.09 Hz, 1 H) 8.06 (d, J = 3.79Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.14 (dd, J = 8.97, 2.40 Hz, 1 H)6.79 (d, J = 3.54 Hz, 1 H) 4.08-4.14 (m, 4 H) 1.96 (s, 3 H) 1.41 (s, 3H) 1.03 (d, J = 2.27 Hz, 2 H) 0.83-0.87 (m, 2 H). 431.18 134-AN

(DMSO-d₆) ppm 8.56 (s, 1 H) 8.28 (s, 1 H) 8.03 (d, J = 3.79 Hz, 1 H)7.47 (d, J = 2.53 Hz, 1 H) 7.13 (dd, J = 9.09, 2.27 Hz, 1 H) 6.77 (d, J= 3.79 Hz, 1 H) 4.10- 4.15 (m, 4 H) 1.43 (s, 9 H) 453.14 134-AO

(DMSO-d₆) ppm 8.55 (s, 1 H) 8.25 (s, 1 H) 8.22 (s, 1 H) 8.05 (d, J =3.54 Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.15 (dd, J = 8.84, 2.53 Hz, 1H) 6.79 (d, J = 3.79 Hz, 1 H) 4.32 (s, 2 H) 4.13 (s, 2 H) 4.09 (d, J =1.77 Hz, 2 H) 3.19 (s, 3 H) 1.40 (s, 9 H) 463.20 134-AP

(DMSO-d₆) ppm 8.57 (s, 1 H) 8.28 (d, J = 9.09 Hz, 1 H) 8.02 (d, J = 3.79Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.14 (dd, J = 8.84, 2.27 Hz, 1 H)6.77 (d, J = 3.54 Hz, 1 H) 4.14 (d, J = 12.88 Hz, 4 H) 1.48 (s, 3 H)1.21-1.25 (m, 2 H) 0.93-0.96 (m, 2 H). 451.12 134-AQ

(DMSO-d₆) ppm 10.69 (s, 1 H) 8.35 (s, 1 H) 8.18 (d, J = 3.79 Hz, 1 H)8.13 (d, J = 9.09 Hz, 1 H) 7.78 (d, J = 2.53 Hz, 1 H) 7.01 (d, J = 8.84Hz, 1 H) 6.80 (d, J = 3.79 Hz, 1 H) 6.52 (d, J = 2.53 Hz, 1 H) 3.82-3.93(m, 2 H) 2.82-2.95 (m, 2 H) 2.31- 2.42 (m, 1 H) 2.21 (s, 3 H) 1.54 (s, 9H) 1.22 (d, J = 6.32 Hz, 3 H) 460.2 134-AR

(DMSO-d₆) ppm 8.40 (s, 1 H) 8.29 (d, J = 8.84 Hz, 1 H) 8.18 (d, J = 3.54Hz, 1 H) 7.42 (d, J = 2.02 Hz, 1 H) 7.06-7.24 (m, 2 H) 6.74 (d, J = 3.79Hz, 1 H) 4.18- 4.37 (m, 2 H) 3.84-3.93 (m, 2 H) 2.95- 2.97 (m, 1 H) 2.85(d, J = 16.67 Hz, 1 H) 2.29-2.35 (m, 1 H) 1.38-1.42 (m, 3 H) 1.21 (d, J= 6.32 Hz, 3 H) 486.1 134-AS

(DMSO-d₆) ppm 11.02 (br. s., 1 H) 8.36 (s, 1 H) 8.02-8.21 (m, 2 H)6.96-7.14 (m, 2 H) 6.85 (d, J = 3.79 Hz, 1 H) 3.5 (s, 3 H) 3.88 (d, J =9.60 Hz, 2 H) 2.93- 3.04 (m, 1 H) 2.89-2.93 (m, 1 H) 2.36- 2.40 (m, 1 H)2.22 (s, 3 H) 1.22 (d, J = 6.32 Hz, 3 H) 486.0 134-AT

(DMSO-d₆) ppm 10.63 (s, 1 H) 8.39 (s, 1 H) 8.28 (d, J = 8.84 Hz, 1 H)8.18 (d, J = 3.79 Hz, 1 H) 7.39 (d, J = 2.27 Hz, 1 H) 7.07 (dd, J =8.97, 2.40 Hz, 1 H) 6.68 (d, J = 3.54 Hz, 1 H) 6.16 (s, 1 H) 4.76 (quin,J = 6.57 Hz, 1 H) 3.77-3.96 (m, 2 H) 2.90-3.03 (m, 1 H) 2.84 (dd, J =16.80, 3.66 Hz, 1 H) 2.33 (dd, J = 16.04, 10.23 Hz, 1 H) 1.86-1.98 (m, 1H) 1.42 (d, J = 6.57 Hz, 6 H) 1.21 (d, J = 6.32 Hz, 3 H) 0.87-1.03 (m, 2H) 0.59-0.76 (m, 2 H) 472.0 134-AU

(DMSO-d₆) ppm 8.36 (s, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 7.85 (d, J = 3.54Hz, 1 H) 7.37 (d, J = 2.27 Hz, 1 H) 7.07 (dd, J = 8.97, 2.15 Hz, 1 H)6.68 (d, J = 3.28 Hz, 1 H) 6.37 (s, 1 H) 3.98 (d, J = 4.55 Hz, 2 H)2.94-3.11 (m, 2 H) 2.41-2.49 (m, 4 H) 1.63 (s, 9 H) 1.32 (d, J = 6.32Hz, 3 H). 460.2

EXAMPLE 135 135-A.(−)-5-((S)-7-Acetyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-cyclopropyl-isoxazol-3-yl)-amide

To a solution of Example 56-S (0.350 g, 0.813 mmol), Et₃N (0.57 mL, 4.07mmol) and DCM (5 mL) is added acetic anhydride (0.084 mL, 0.894 mmol).After 0.5 h the solution is concentrated and the residue partitionedbetween DCM and saturated NaHCO₃. The organic layer is washed withbrine. Following drying the organic layer is concentrated and theresidue separated via FCC (1-10% MeOH/DCM) to give the title compound.MS (ESI) m/z 473.2 (M+1); At 27° C. in DMSO-d₆ solution Example 135-Aexists as a mixture of amide rotamers. While not wishing to be bound bytheory, hindered rotation about the nitrogen carbonyl bond results intwo magnetically distinct environments for some protons. ¹H NMR isacquired at 80° C. which is above the temperature at which the separaterotamer ¹H peaks coalesce. (400 MHz, DMSO-d₆) δ ppm 10.95 (br. S., 1H)8.50 (s, 1H) 8.28 (d, J=8.97 Hz, 1H) 8.13 (d, J=3.66 Hz, 1H) 7.45 (d,J=2.27 Hz, 1H) 7.14 (dd, J=9.03, 2.34 Hz, 1H) 6.73 (d, J=3.66 Hz, 1H)6.59 (s, 1H) 4.61-5.43 (m, 2H) 4.22 (br. S., 1H) 2.99 (br. S., 1H)2.79-2.89 (m, 1H) 2.11-2.19 (m, 4H) 1.17 (d, J=7.33 Hz, 3H) 1.06-1.13(m, 2H) 0.91-0.96 (m, 2H).

The following compounds are prepared with similar method. Such compoundsare also prepared from the corresponding carboxylic acid and amine usingpeptide coupling reagents (e.g. HATU see Example 40) or using thecorresponding carboxylic acid chloride. Example 135-BN is prepared withsimilar method using ethyl chloroformate. For Examples 135-I, J, L, P,AC, AD, AE, AF, AG, AH removal of a BOC group from the nitrogenfollowing amide formation is accomplished via treatment of the parentcompound with TFA in DCM as described in previous examples.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 135-B^(a)

(DMSO-d₆) δ ppm 11.22 (s, 1 H), 8.52 (br. S.), 8.28 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 3.5 Hz, 1 H), 7.46 (d, J = 2.5 Hz, 1 H), 7.15 (dd, J =9.0, 2.4 Hz, 1 H), 6.76 (d, J = 3.3 Hz, 1 H), 6.65 (s, 1 H), 5.16- 5.22(m), 5.13 (d), 4.73-4.79 (m), 4.48- 4.63 (m), 4.04 (d), 3.04-3.15 (m),2.78-2.88 (m), 2.09-2.23 (m), 1.21 (d, J = 6.6 Hz, 2 H), 1.03-1.13 (m, 3H), 0.89-0.98 (m, 2 H) 473.0 135-C^(b)

(110° C.; DMSO-d₆) δ ppm 10.33 (br. S., 1 H) 8.50 (s, 1 H) 8.29 (d, J =8.97 Hz, 1 H) 8.11 (d, J = 3.79 Hz, 1 H) 7.45 (d, J = 2.27 Hz, 1 H) 7.14(dd, J = 8.97, 2.40 Hz, 1H) 6.96 (s, 1 H) 6.73 (d, J = 3.66 Hz, 1 H)4.98 (d, J = 19.71 Hz, 1 H) 4.87 (br. S., 1 H) 4.26 (d, J = 17.68 Hz, 1H) 2.97-3.07 (m, 1 H) 2.88 (br. S., 1 H) 2.15 (s, 3 H) 1.49-1.60 (m, 4H) 1.19 (d, J = 6.82 Hz, 3 H) 541.1 135-D^(a)

(DMSO-d₆) δ ppm 11.22 (s, 1 H), 8.51 (s, 1 H), 8.28 (d, J = 9.1 Hz, 1H), 8.16 (d, J = 3.5 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H), 7.16 (dd, J =9.0, 2.4 Hz, 1 H), 6.76 (d, J = 3.5 Hz, 1 H), 6.65 (s, 1 H), 4.97- 5.24(m), 4.52-4.74 (m), 4.03-4.23 (m), 2.99-3.17 (m), 2.76-2.96 (m),2.14-2.23 (m), 2.02-2.16 (m), 1.19- 1.32 (m), 1.05-1.13 (m), 0.91-0.98(m), 0.81-0.89 (m), 0.71-0.81 (m) 499.1 135-E^(b)

(110° C.; DMSO-d₆) δ ppm 10.98 (br. S., 1 H) 8.50 (s, 1 H) 8.28 (d, J =8.84 Hz, 1 H) 8.11 (d, J = 3.54 Hz, 1 H) 7.46 (d, J = 1.77 Hz, 1 H) 7.15(dd, J = 8.84, 1.77 Hz, 1 H) 6.96 (s, 1 H) 6.74 (d, J = 3.54 Hz, 1 H)5.02 (d, J = 18.69 Hz, 1 H) 4.92 (br. S., 1 H) 4.25 (d, J = 18.95 Hz, 1H) 2.95-3.05 (m, 1 H) 2.83 (br. S., 1 H) 2.35 (d, J = 5.68 Hz, 2 H)2.07- 2.17 (m, 1 H) 1.48-1.62 (m, 4 H) 1.19 (d, J = 6.69 Hz, 3 H) 0.98(d, J = 5.05 Hz, 6 H) 583.2 135-F

(DMSO-d₆) δ ppm 11.43 (s, 1 H) 8.49 (s, 1 H) 8.29 (d, J = 9.09 Hz, 1 H)8.16 (d, J = 3.54 Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.16 (dd, J =8.97, 2.40 Hz, 1 H) 7.04 (s, 1 H) 6.77 (d, J = 3.79 Hz, 1 H) 5.10 (d, J= 19.20 Hz, 1 H) 4.94-5.06 (m, 1 H) 4.17 (d, J = 19.20 Hz, 1 H)2.93-3.04 (m, 1 H) 2.81 (d, J = 16.93 Hz, 1 H) 1.53-1.60 (m, 4 H) 1.27(s, 9 H) 1.21 (d, J = 6.82 Hz, 3 H) 583.2 135-G

(DMSO-d₆) δ ppm 11.22 (s, 1 H), 8.50 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 3.8 Hz, 1 H), 7.45 (d, J = 2.3 Hz, 1 H), 7.14 (dd, J =9.0, 2.4 Hz, 1 H), 6.76 (d, J = 3.5 Hz, 1 H), 6.65 (s, 1 H), 4.59-4.71(m, 2 H), 3.81 (t, J = 5.8 Hz, 2 H), 2.76- 2.98 (m, 2 H), 2.08-2.26 (m,4 H), 1.05- 1.15 (m, 2 H), 0.89-0.98 (m, 2 H) 459.2 135-H

(DMSO-d₆) δ ppm 11.27 (s, 1 H), 8.48 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 3.8 Hz, 1 H), 7.45 (d, J = 2.5 Hz, 1 H), 7.14 (dd, J =8.8, 2.3 Hz, 1 H), 6.76 (d, J = 3.8 Hz, 1 H), 6.68 (s, 1 H), 4.62 (s, 1H), 3.75-3.85 (m, 2 H), 2.89-2.97 (m, 2 H), 2.15 (s, 3 H), 1.34 (s, 9 H)475.2 135-I

(DMSO-d₆) δ ppm 8.50 (s, 1 H) 8.35 (d, J = 8.84 Hz, 1 H) 8.14 (d, J =3.54 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1 H) 7.12 (dd, J = 8.84, 2.27 Hz, 1H) 7.03 (s, 1 H) 6.70 (d, J = 3.54 Hz, 1 H) 5.18 (br. S., 2 H) 4.25 (br.S., 1 H) 2.93-3.20 (m, 1 H) 2.80 (d, J = 16.67 Hz, 1 H) 1.45-1.60 (m, 5H) 1.20 (d, J = 6.57 Hz, 3 H) 0.94- 1.04 (m, 1 H) 0.81-0.90 (m, 1 H)0.65- 0.79 (m, 2 H) 581.9 135-J

(DMSO-d₆) δ ppm 8.50 (s, 1 H) 8.33 (d, J = 8.84 Hz, 1 H) 8.15 (d, J =3.79 Hz, 1 H) 7.45 (d, J = 2.27 Hz, 1 H) 7.13 (dd, J = 8.97, 2.40 Hz, 1H) 7.03 (s, 1 H) 6.73 (d, J = 3.54 Hz, 1 H) 5.48 (br. S., 2 H) 4.21 (br.S., 1 H) 3.00 (br. S., 1 H) 2.78 (d, J = 17.18 Hz, 1 H) 1.50-1.59 (m, 4H) 1.42 (s, 6 H) 1.20 (d, J = 6.82 Hz, 3 H) 583.9 135-K^(a)

(DMSO-d₆) δ ppm 11.22 (s, 1 H), 8.50 (br. S., 1 H), 8.29 (d, J = 9.1 Hz,1 H), 8.15 (d, J = 3.5 Hz, 1 H), 7.46 (d, J = 2.3 Hz, 1 H), 7.14 (dd, J= 9.0, 2.4 Hz, 1 H), 6.75 (d, J = 3.5 Hz, 1 H), 6.65 (s, 1 H), 5.20-5.29(m), 5.16 (d, J = 18.9 Hz), 4.81 (d, J = 18.4 Hz), 4.61-4.72 (m), 4.49(d, J = 19.2 Hz), 4.05 (d, J = 19.2 Hz), 2.97-3.09 (m), 2.75-2.88 (m),2.29-2.40 (m), 2.12-2.22 (m, 1 H), 1.98-2.11 (m, 1 H), 1.20 (d, J = 6.1Hz, 2 H), 1.02-1.13 (m, 4 H), 0.89-0.99 (m, 9 H) 499.1 135-L^(a)

(DMSO-d₆) δ ppm 8.51 (s, 1 H), 8.34 (d, J = 9.1 Hz, 1 H), 8.13 (d, J =3.5 Hz, 1 H), 7.43 (d, J = 2.3 Hz, 1 H), 7.10 (dd, J = 9.0, 2.4 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1 H), 6.63 (s, 1 H), 5.07-5.53 (m), 4.65-4.81(m), 4.37-4.61 (m), 4.04-4.19 (m) 3.43-3.69 (m), 2.99-3.18 (m),2.76-2.91 (m), 2.07-2.20 (m), 1.09- 1.26 (m), 1.02-1.09 (m, 2 H), 0.86-0.94 (m, 2 H) 488.1 135-M^(a)

(DMSO-d₆) δ ppm 11.22 (s, 1 H), 8.50 (br. S., 1 H), 8.28 (d, J = 9.1 Hz,1 H), 8.16 (d, J = 3.8 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1 H), 7.15 (dd, J =9.0, 2.4 Hz, 1 H), 6.75 (d, J = 3.5 Hz, 1 H), 6.65 (s, 1 H), 5.10-5.31(m), 4.87 (d), 4.66-4.78 (m), 4.54 (d), 4.06 (d), 2.94-3.13 (m),2.76-2.92 (m), 2.10-2.24 (m), 1.23 (d, J = 6.6 Hz, 2 H), 1.04-1.13 (m),0.97-1.03 (m), 0.88-0.97 (m, 2 H) 501.1 135-N

(DMSO-d₆) δ ppm 11.04 (br. S., 1 H), 8.48 (s, 1 H), 8.30 (d, J = 9.1 Hz,1 H), 8.17 (d, J = 3.8 Hz, 1 H), 7.45 (d, J = 2.3 Hz, 1 H), 7.13 (d, J =9.1 Hz, 1 H), 6.76 (d, J = 3.5 Hz, 1 H), 6.68 (s, 1 H), 4.64 (s, 2 H),3.84 (q, J = 6.0 Hz, 2 H), 2.93 (t, J = 4.9 Hz, 1 H), 2.71-2.84 (m, 3H), 2.52-2.66 (m, 6 H), 1.34 (s, 9 H), 0.90- 1.03 (m, 6 H) 560.3 135-O

(DMSO-d₆) δ ppm 10.55 (br. S., 1 H), 8.47 (s, 1 H), 8.30 (d, J = 8.8 Hz,1 H), 8.17 (d, J = 3.3 Hz, 2 H), 7.42 (s, 1 H), 7.10 (d, J = 7.8 Hz, 1H), 6.65-6.73 (m, 1 H), 6.30 (s, 1 H), 4.61 (s, 2 H), 3.74- 3.85 (m, 2H), 2.88-2.97 (m, 1 H), 2.76-2.84 (m, 1 H), 2.15 (s, 3 H), 1.41 (s, 3H), 0.89-0.97 (m, 2 H), 0.73- 0.80 (m, 2 H) 472.3 135-P^(b)

(80° C. DMSO-d₆) δ ppm 8.51 (s, 1 H) 8.35 (d, J = 8.84 Hz, 1 H) 8.12 (d,J = 3.66 Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1 H) 7.10 (dd, J = 8.91, 2.34Hz, 1 H) 6.98 (s, 1 H) 6.68 (d, J = 3.66 Hz, 1 H) 5.28 (br. S., 2 H)4.94 (br. S., 2 H) 4.16-4.41 (m, 1 H) 2.96-3.01 (m, 1 H) 2.79-2.92 (m, 1H) 1.47-1.57 (m, 4 H) 1.19 (d, J = 7.07 Hz, 3 H) 556.1 135-Q^(b)

(100° C. DMSO-d₆) δ ppm 11.04 (br. S., 1 H) 8.50 (s, 1 H) 8.28 (d, J =8.84 Hz, 1 H) 8.12 (d, J = 3.79 Hz, 1 H) 7.46 (d, J = 2.15 Hz, 1 H) 7.15(dd, J = 8.84, 2.27 Hz, 1 H) 6.97 (s, 1 H) 6.75 (d, J = 3.66 Hz, 1 H)5.05 (d, J = 18.95 Hz, 1 H) 4.94 (br. S., 1 H) 4.26 (d, J = 18.95 Hz, 1H) 2.97-3.05 (m, 2 H) 2.81-2.91 (m, 1 H) 1.47-1.61 (m, 4 H) 1.20 (d, J =6.69 Hz, 3 H) 1.10 (t, J = 7.14 Hz, 6 H) 569.2 135-R^(b)

(80° C. DMSO-d₆) δ ppm 11.17 (br. S., 1 H) 8.51 (s, 1 H) 8.30 (d, J =8.97 Hz, 1 H) 8.13 (d, J = 3.79 Hz, 1 H) 7.46 (d, J = 2.15 Hz, 1 H) 7.15(dd, J = 8.97, 2.40 Hz, 1 H) 6.99 (s, 1 H) 6.74 (d, J = 3.16 Hz, 1 H)5.11 (d, J = 18.95 Hz, 2 H) 4.33 (d, J = 18.57 Hz, 1 H) 2.99-3.04 (m, 1H) 2.85-2.92 (m, 1 H) 2.03-2.12 (m, 1 H) 1.50-1.59 (m, 4 H) 1.20 (d, J =6.82 Hz, 3 H) 0.78-0.89 (m, 4 H) 567.2 135-S^(a)

(DMSO-d₆) δ ppm 11.27 (s, 1 H), 8.52 (br. S.), 8.50 (s), 8.29 (d, J =9.1 Hz, 1 H), 8.17 (d, J = 3.5 Hz, 1 H), 7.47 (d, J = 2.5 Hz, 1 H), 7.15(dd, J = 8.8, 2.5 Hz, 1 H), 6.76 (d, J = 3.8 Hz, 1 H), 6.68 (s, 1 H),5.16-5.24 (m), 5.13 (d, J = 19.5 Hz), 4.70-4.82 (m), 4.47-4.64 (m), 4.05(d, J = 19.7 Hz), 3.02-3.16 (m), 2.77-2.89 (m), 2.17 (s), 2.12 (s), 1.34(s), 1.21 (d, J = 6.6 Hz), 1.07 (d, J = 6.8 Hz) 489.1 135-T^(a)

(DMSO-d₆) δ ppm 11.26 (s, 1 H), 8.52 (br. S.), 8.50 (s), 8.29 (d, J =8.8 Hz, 1 H), 8.17 (d, J = 3.8 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H), 7.15(dd, J = 9.0, 2.4 Hz, 1 H), 6.76 (d, J = 3.8 Hz, 1 H), 6.70 (s, 1 H),5.16-5.22 (m), 5.13 (d, J = 19.7 Hz), 4.76 (d, J = 18.7 Hz), 4.56-4.64(m), 4.43-4.55 (m), 4.05 (d, J = 20.0 Hz), 3.03-3.17 (m, 2 H), 2.77-2.87(m), 2.17 (s), 2.12 (s), 1.29 (d, J = 6.8 Hz, 6 H), 1.21 (d, J = 6.8Hz), 1.07 (d, J = 6.8 Hz) 475.1 135-U^(a)

(DMSO-d₆) δ ppm 11.19 (br. S., 1 H), 8.49 (s, 1 H), 8.29 (d, J = 8.8 Hz,1 H), 8.15 (d, J = 3.8 Hz, 1 H), 7.45 (d, J = 2.3 Hz, 1 H), 7.13 (dd, J= 9.0, 2.4 Hz, 1 H), 6.74 (d, J = 3.5 Hz, 1 H), 6.65 (s, 1 H), 5.18 (br.S.), 5.14 (d, J = 19.5 Hz), 4.59 (d, J = 18.7 Hz), 4.33-4.50 (m), 4.06(d, J = 19.5 Hz), 3.40-3.59 (m, 1 H), 2.92- 3.04 (m), 2.71-2.90 (m),2.04-2.36 (m), 1.86-2.02 (m), 1.67-1.83 (m, 1 H), 1.18 (d, J = 6.8 Hz),1.01-1.11 (m), 0.89-0.98 (m) 513.2 135-V^(a)

(DMSO-d₆) δ ppm 10.38 (s, 1 H), 8.52 (br. S.), 8.50 (s), 8.27 (d, J =9.1 Hz, 1 H), 8.12 (d, J = 3.5 Hz, 1 H), 8.10 (s, 1 H), 7.97 (d, J =10.1 Hz, 1 H), 7.65 (app t, J = 8.0 Hz, 1 H), 7.48-7.54 (m, 1 H),7.43-7.52 (m, 2 H), 7.15 (dd, J = 8.8, 2.3 Hz, 1 H), 6.80 (d, J = 3.5Hz, 1 H), 5.17-5.23 (m), 5.13 (d, J = 18.7 Hz), 4.69-4.81 (m), 4.43-4.65(m), 4.05 (d, J = 19.5 Hz), 3.02-3.14 (m), 2.78-2.89 (m), 2.17 (br. S.),2.12 (br. S.), 1.21 (d, J = 6.6 Hz), 1.08 (d, J = 6.8 Hz) 510.1135-W^(a)

(DMSO-d₆) δ ppm 11.22 (s, 1 H), 8.52 (br. S), 8.50 (s), 8.28 (d, J = 9.1Hz, 1 H), 8.16 (d, J = 3.8 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H), 7.15(dd, J = 9.0, 2.4 Hz, 1 H), 6.76 (d, J = 3.5 Hz, 1 H), 6.65 (s, 1 H),5.24-5.30 (m), 5.20 (d, J = 19.5 Hz), 4.85-4.98 (m), 4.70-4.84 (m), 4.52(d, J = 16.4 Hz), 4.07 (d, J = 18.7 Hz), 2.98-3.10 (m), 2.74-2.92 (m),2.08- 2.24 (m, 1 H), 1.46-1.73 (m), 1.26- 1.46 (m), 1.22 (d, J = 6.6Hz), 1.01- 1.13 (m), 0.91-0.99 (m), 0.87 (t, J = 7.3 Hz), 0.73-0.83 (m)515.3 135-X^(a)

(DMSO-d₆) δ ppm 10.63 (s, 1 H), 8.52 (br. S.), 8.49 (s), 8.30 (d, J =9.1 Hz, 1 H), 8.16 (d, J = 3.5 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.11(dd, J = 9.0, 2.4 Hz, 1 H), 6.71 (d, J = 3.8 Hz, 1 H), 6.40 (s, 1 H),5.16-5.23 (m), 5.12 (d, J = 19.7 Hz), 4.76 (d, J = 17.4 Hz), 4.55-4.64(m), 4.43-4.55 (m), 4.04 (d, J = 19.7 Hz), 3.96 (t, J = 6.2 Hz, 2 H),3.00- 3.14 (m), 2.75-2.87 (m), 2.17 (s), 2.12 (s), 1.96-2.06 (m, 2 H),1.61-1.72 (m, 2 H), 1.30 (s, 6 H), 1.21 (d, J = 6.8 Hz), 1.07 (d, J =6.6 Hz) 514.1 135-Y^(a)

(DMSO-d₆) δ ppm 10.63 (s, 1 H), 8.52 (br. S.), 8.49 (s), 8.28 (d, J =9.1 Hz, 1 H), 8.15 (d, J = 3.5 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.11(dd, J = 9.0, 2.4 Hz, 1 H), 6.71 (d, J = 3.8 Hz, 1 H), 6.28 (s, 1 H),5.15-5.24 (m), 5.12 (d, J = 19.7 Hz), 4.76 (d, J = 18.9 Hz), 4.55-4.62(m), 4.46-4.56 (m), 4.09 (t, J = 6.9 Hz, 2 H), 3.04-3.14 (m), 2.77-2.89(m), 2.34 (t, J = 6.8 Hz, 2 H), 2.17 (s), 2.12 (s), 1.32 (s, 6 H), 1.21(d, J = 6.8 Hz), 1.07 (d, J = 6.8 Hz) 500.1 135-Z^(a)

(DMSO-d₆) δ ppm 10.63 (s, 1 H), 8.51 (s, 1 H), 8.28 (d, J = 9.1 Hz, 1H), 8.15 (d, J = 3.5 Hz, 1 H), 7.45 (d, J = 2.5 Hz, 1 H), 7.12 (dd, J =9.0, 2.4 Hz, 1 H), 6.71 (d, J = 3.5 Hz, 1 H), 6.27 (s, 1 H), 4.96- 5.27(m), 4.42-4.73 (m), 4.09 (app t, J = 6.9 Hz, 2 H), 2.99-3.17 (m), 2.76-2.95 (m), 2.28-2.39 (m), 2.07-2.21 (m), 1.24 (br. S.), 1.03-1.15 (m),0.81- 0.91 (m), 0.70-0.81 (m) 526.2 135-AA^(a)

(DMSO-d₆) δ ppm 10.71 (s, 1 H) 8.42- 8.59 (m, 1 H) 8.31 (d, J = 9.09 Hz,1 H) 8.21 (d, J = 3.54 Hz, 1 H) 7.78 (d, J = 2.27 Hz, 1 H) 7.44 (d, J =2.27 Hz, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1 H) 6.70 (d, J = 3.54 Hz, 1H) 6.52 (d, J = 2.53 Hz, 1 H) 5.02-2.77 [2 sets of signals are observedat about 3/2 ratio, totally 5 H; 5.02-5.27 (m) 4.76 (d, J = 18.44 Hz)4.43-4.64 (m) 4.05 (d, J = 19.20 Hz) 3.01-3.13 (m,) 2.77-2.91 (m)] [2.17(s) 2.12 (s) totally 3 H] 1.54 (s, 9 H) [1.21 (d, J = 6.57 Hz) 1.07 (d,J = 6.57 Hz) totally 3 H] 488.1 135-AB

(DMSO-d₆) δ ppm 12.13 (br. S., 1 H), 10.56 (br. S., 1 H), 8.48 (s, 1 H),8.30 (d, J = 8.8 Hz, 1 H), 8.17 (d, J = 3.3 Hz, 1 H), 7.42 (d, J = 2.0Hz, 1 H), 7.09 (d, J = 9.1 Hz, 1 H), 6.71 (d, J = 3.5 Hz, 1 H), 6.29(br. S., 1 H), 4.63 (s, 2 H), 3.77-3.89 (m, 2 H), 2.89-2.96 (m, 1 H),2.76-2.83 (m, 1 H), 2.64-2.74 (m, 2 H), 2.51-2.61 (m, 6 H), 1.41 (s, 3H), 0.87-1.01 (m, 8 H), 0.74-0.82 (m, 2 H) 557.3 135-AC

Complex NMR due to the existanc of both rotamers and diastereomers.514.1 135-AD

(DMSO-d₆) δ ppm 11.20 (br. S., 1 H) 8.50 (s, 1 H) 8.28 (d, J = 9.09 Hz,1 H) 8.16 (d, J = 3.54 Hz, 1 H) 7.46 (d, J = 2.53 Hz, 1 H) 7.15 (dd, J =8.97, 2.40 Hz, 1 H) 6.75 (d, J = 3.54 Hz, 1 H) 6.65 (s, 1 H) 5.18 (br.S., 2 H) 4.26 (br. S., 1 H) 3.06 (br. S., 1 H) 2.80 (d, J = 16.93 Hz, 1H) 2.35 (br. S., 1 H) 2.09-2.24 (m, 1 H) 1.16-1.27 (m, 3 H) 1.05-1.14(m, 2 H) 0.91-1.03 (m, 3 H) 0.81-0.90 (m, 1 H) 0.65-0.79 (m, 2 H) 514.1135-AE

(DMSO-d₆) δ ppm 8.49 (s, 1 H) 8.29 (d, J = 8.84 Hz, 1 H) 8.15 (d, J =3.79 Hz, 1 H) 7.45 (d, J = 2.53 Hz, 1 H) 7.13 (dd, J = 8.97, 2.40 Hz, 1H) 6.74 (d, J = 3.79 Hz, 1 H) 6.65 (s, 1 H) 4.09-4.32 (m, 2 H) 2.93-3.13 (m, 2 H) 2.76 (d, J = 17.18 Hz, 2 H) 2.64-2.69 (m, 1 H) 2.10-2.22(m, 1 H) 1.36 (d, J = 4.80 Hz, 6 H) 1.19 (d, J = 6.82 Hz, 3 H) 1.03-1.12(m, 2 H) 0.90-0.98 (m, 2 H) 516.1 135-AF^(a)

(DMSO-d₆) δ ppm 8.50 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 8.14 (d, J =3.8 Hz, 1 H), 7.44 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.71 (d, J = 3.5 Hz, 1 H), 6.27 (s, 1 H), 5.06-5.25 (m), 4.64- 4.83(m), 4.39-4.61 (m), 4.11-4.15 (m), 4.09 (t, J = 6.8 Hz, 2 H), 3.37-3.61(m), 2.97-3.14 (m), 2.84 (br. S.), 2.79 (br. S.), 2.30-2.38 (m, 2 H),1.32 (s, 6 H), 1.15-1.25 (m), 1.02-1.13 (m). 515.2 135-AG^(a)

(DMSO-d₆) δ ppm 8.53 (s), 8.46 (s) 8.33 (d, J = 9.09 Hz, 1 H) 8.14 (d, J= 3.79 Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1 H) 7.10 (dd, J = 8.97. 2.40 Hz,1 H) 6.70 (d, J = 3.54 Hz, 1 H) 6.63 (s, 1 H) 5.17 (m) 5.15 (d, J =19.20 Hz) 4.43 (m) 4.24-4.31 (m) 4.10 (d, J = 19.45) 3.82-3.96 (m)3.63-3.81 (m) 2.94-3.06 (m) 2.72-2.89 (m) 2.08- 2.19 (m, 1 H) 1.18 (d, J= 6.82 Hz) 1.02- 1.13 (m) 0.84-0.96 (m) 514.1 135-AH

(DMSO-d₆) δ ppm 10.63 (s, 1 H), 8.51 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 3.8 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.12 (dd, J =9.0, 2.4 Hz, 1 H), 6.71 (d, J = 3.3 Hz, 1 H), 6.27 (s, 1 H), 5.28 (br.S., 1 H), 4.27 (br. S., 1 H), 4.09 (t, J = 6.8 Hz, 2 H), 2.95-3.12 (m, 1H), 2.81 (d, J = 16.7 Hz, 1 H), 2.27-2.37 (m, 2 H), 1.50 (br. S., 6 H),1.32 (s, 6 H), 1.22 (d, J = 6.6 Hz, 3 H) 543.2 135-AI^(a)

(DMSO-d₆) δ ppm 10.56 (s, 1 H), 8.52 (br. S.), 8.50 (s), 8.30 (d, J =8.8 Hz, 1 H), 8.17 (d, J = 3.3 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.11(dd, J = 9.1, 2.3 Hz, 1 H), 6.70 (d, J = 3.8 Hz, 1 H), 6.29 (s, 1 H),5.16-5.25 (m), 5.12 (d, J = 19.7 Hz), 4.76 (d, J = 18.7 Hz), 4.55-4.63(m), 4.48-4.54 (m), 4.04 (d, J = 19.5 Hz), 3.03-3.15 (m), 2.74-2.88 (m),2.17 (s), 2.12 (s), 1.41 (s, 3 H), 1.21 (d, J = 6.6 Hz), 1.07 (d, J =6.8 Hz), 0.89- 0.97 (m, 2 H), 0.74-0.80 (m, 2 H) 486.2 135-AJ^(a)

(DMSO-d₆) δ ppm 10.60 (s, 1 H), 8.50- 8.55 (m), 8.49 (s), 8.29 (d, J =9.0 Hz, 1 H), 8.16 (d, J = 3.5 Hz, 1 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.11(dd, J = 9.0, 2.4 Hz, 1 H), 6.71 (d, J = 3.7 Hz, 1 H), 6.28 (s, 1 H),5.06-5.23 (m), 4.70-4.82 (m), 4.40-4.66 (m), 3.94-4.11 (m), 3.03- 3.14(m), 2.78-2.91 (m), 2.17 (s), 2.12 (s), 1.21 (d, J = 6.3 Hz), 1.00-1.10(m) 472.2 135-AK^(a)

Due to the existance of rotamers about the amide bond the ¹H NMR iscomplex when taken at 27° C., thus only a partial listing of NMR signalsare reported. (DMSO-d₆) δ ppm 11.22 (s, 1 H), 8.51 (s, 1 H), 8.28 (d, J= 9.1 Hz, 1 H), 8.16 (d, J = 3.8 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H),7.15 (dd, J = 9.0, 2.4 Hz, 1 H), 6.76 (d, J = 3.3 Hz, 1 H), 6.65 (s, 1H), 2.11-2.25 (m, 1 H), 1.20 (s, 6 H), 1.13 (s, 6 H) 555.3 135-AL^(a)

(DMSO-d₆) δ ppm 11.23 (s, 1 H), 8.52 (br. S.), 8.50 (s), 8.28 (d, J =8.8 Hz, 1 H), 8.16 (d, J = 3.8 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H), 7.15(dd, J = 9.0, 2.4 Hz, 1 H), 6.76 (d, J = 3.8 Hz, 1 H), 6.71 (s, 1 H),5.17-5.25 (m), 5.06-5.17 (m), 4.76 (d, J = 18.9 Hz), 4.42-4.64 (m), 4.05(d, J = 19.2 Hz), 3.02-3.16 (m), 2.73-2.89 (m), 2.44 (s, 3 H), 2.17 (s),2.12 (s), 1.21 (d, J = 6.8 Hz), 1.07 (d, J = 6.8 Hz) 447.0 135-AM

(DMSO-d₆) δ ppm 11.24 (s, 1 H) 8.66 (d, J = 8.34 Hz, 1 H) 8.30 (d, J =9.09 Hz, 1 H) 8.17 (d, J = 3.79 Hz, 1 H) 7.50 (d, J = 2.27 Hz, 1 H) 7.18(dd, J = 8.84, 2.27 Hz, 1 H) 6.78 (d, J = 3.28 Hz, 1 H) 6.65 (s, 1 H)5.15 (s, 1 H) 5.07 (s, 1 H) 4.67 (br. S., 2 H) 2.10-2.25 (m, 1 H) 1.85-2.08 (m, 1 H) 1.09 (dd, J = 8.59, 2.53 Hz, 1 H) 1.02-1.18 (m, 1 H)0.88-1.00 (m, 2 H) 0.83 (dd, J = 6.32, 2.53 Hz, 4 H) 471.0 135-AN

(DMSO-d₆) δ ppm 11.24 (s, 1 H) 8.66 (d, J = 7.33 Hz, 1 H) 8.30 (d, J =8.59 Hz, 1 H) 8.17 (d, J = 4.04 Hz, 1 H) 7.50 (t, J = 2.27 Hz, 1 H)7.16-7.20 (m, 1 H) 6.78 (dd, J = 3.54, 2.02 Hz, 1 H) 6.65 (s, 1 H) 5.03(s, 1 H) 4.95 (s, 1 H) 4.65 (d, J = 7.07 Hz, 2 H) 3.36-3.38 (m, 1 H)2.12-2.15 (m, 1 H) 1.09 (dd, J = 6.57, 5.56 Hz, 8 H) 0.92-0.97 (m, 2 H)473.0 135-AO

(DMSO-d₆) δ ppm 10.27 (s, 1 H) 8.66 (d, J = 5.56 Hz, 1 H) 8.27 (dd, J =8.84, 2.78 Hz, 1 H) 8.10 (d, J = 3.79 Hz, 1 H) 7.92-8.05 (m, 1 H) 7.69(t, J = 6.82 Hz, 1 H) 7.46-7.55 (m, 1 H) 7.16 (dd, J = 4.80, 2.27 Hz, 1H) 7.18 (dd, J = 4.80, 2.53 Hz, 1 H) 6.82 (d, J = 1.26 Hz, 1 H) 4.97 (s,1 H) 4.90 (s, 1 H) 4.63 (d, J = 3.79 Hz, 2 H) 2.11 (d, J = 6.57 Hz, 3 H)500.9 135-AP

(DMSO-d₆) δ ppm 11.13 (br. S., 1 H) 8.59 (d, J = 5.05 Hz, 1 H) 8.22 (d,J = 2.02 Hz, 1 H) 8.10 (d, J = 3.54 Hz, 1 H) 7.42 (br. S., 1 H) 7.10(td, J = 4.29, 2.78 Hz, 1 H) 6.69 (br. S., 1 H) 6.58 (s, 1 H) 4.90 (s, 1H) 4.83 (s, 1 H) 4.56 (br. S., 2 H) 2.04 (d, J = 5.81 Hz, 3 H) 2.01-2.14(m, 1 H) 1.02 (dd, J = 8.34, 2.27 Hz, 2 H) 0.87 (dd, J = 4.55, 2.27 Hz,2 H) 445.9 135-AQ

(DMSO-d₆) δ ppm 11.26 (br. S., 1 H) 8.66 (d, J = 5.05 Hz, 1 H) 8.31 (dd,J = 9.09, 2.53 Hz, 1 H) 8.18 (d, J = 3.79 Hz, 1 H) 7.50 (d, J = 2.78 Hz,1 H) 7.15- 7.23 (m, 1 H) 6.77 (d, J = 2.53 Hz, 1 H) 6.69 (s, 1 H) 4.97(s, 1 H) 4.90 (s, 1 H) 4.64 (s, 2 H) 3.10 (d, J = 7.33 Hz, 1 H) 2.11 (d,J = 6.32 Hz, 3 H) 1.29 (d, J = 7.07 Hz, 6 H) 447.9 135-AR

(DMSO-d₆) δ ppm 11.28 (s, 1 H) 8.66 (d, J = 7.07 Hz, 1 H) 8.31-8.33 (m,1H) 8.18 (d, J = 4.04 Hz, 1 H) 7.50 (t, J = 2.27 Hz, 1 H) 7.16-7.20 (m,1 H) 6.79 (d, J = 1.77 Hz, 1 H) 6.70 (s, 1 H) 5.03 (s, 1 H) 4.95 (d, J =1.26 Hz, 1 H) 4.65 (s, 2 H) 3.08-3.15 (m, 1 H) 2.79-2.85 (m, 1 H) 1.29(d, J = 6.82 Hz, 6 H) 1.09 (d, J = 5.31 Hz, 2 H) 1.08 (d, J = 5.56 Hz, 4H) 475.9 135-AS

(DMSO-d₆) δ ppm 11.25 (br. S., 1 H) 8.66 (d, J = 4.80 Hz, 1 H) 8.24-8.42(m, 1 H) 8.17 (d, J = 3.54 Hz, 1 H) 7.49 (d, J = 3.28 Hz, 1 H) 7.17 (d,J = 6.06 Hz, 1 H) 6.77 (br. S., 1 H) 6.67 (s, 1 H) 4.97 (s, 1 H) 4.90(br. S., 1 H) 4.64 (br. S., 2 H) 2.10-2.11 (m, 3 H) 1.46 (s, 3 H) 1.15(d, J = 2.27 Hz, 2 H) 0.93 (d, J = 2.53 Hz, 2 H) 459.9 135-AT

(DMSO-d₆) δ ppm 11.25 (s, 1 H) 8.66 (d, J = 8.34 Hz, 1 H) 8.28-8.31 (m,1 H) 8.18 (d, J = 3.79 Hz, 1 H) 7.50 (d, J = 2.27 Hz, 1 H) 7.17-7.18 (m,1 H) 6.78 (d, J = 3.28 Hz, 1 H) 6.67 (s, 1 H) 5.15 (s, 1 H) 5.07 (s, 1H) 4.67 (br. S., 2H) 1.92- 1.99 (m, 1H) 1.46 (s, 3 H) 1.16 (d, J = 2.53Hz, 2H) 1.16 (d, J = 10.86 Hz, 1 H) 0.94 (d, J = 2.27 Hz, 1 H) 0.89-0.99(m, 1 H) 0.83 (d, J = 3.03 Hz, 1 H) 0.83 (d, J = 8.84 Hz, 2 H) 485.9135-AU

(DMSO-d₆) δ ppm 11.25 (s, 1 H) 8.66 (d, J = 7.07 Hz, 1 H) 8.30-8.31 (m,1 H) 8.18 (d, J = 3.79 Hz, 1 H) 7.41-7.59 (m, 1 H) 7.10-7.29 (m, 1 H)6.79 (d, J = 2.02 Hz, 1 H) 6.67 (s, 1 H) 5.03 (s, 1 H) 4.96 (s, 1 H)4.65 (s, 2 H) 2.84 (dd, J = 16.17, 6.82 Hz, 1 H) 1.46 (s, 3 H) 1.15-1.17(m, 2 H) 1.07-1.10 (m, 6 H) 0.93-0.95 (m, 2 H) 487.9 135-AV

(DMSO-d₆) δ ppm 11.19 (br. S., 1 H) 8.59 (d, J = 5.05 Hz, 1 H) 8.23-8.25(m, 1 H) 8.11 (d, J = 3.79 Hz, 1 H) 7.43 (br. S., 1 H) 7.43 (d, J = 5.56Hz, 1 H) 7.08- 7.18 (m, 1 H) 6.70 (br. S., 1 H) 6.71 (d, J = 1.52 Hz, 1H) 6.61 (s, 2 H) 4.90 (s, 2 H) 4.83 (s, 2 H) 4.57 (s, 3 H) 2.04 (d, J =6.32 Hz, 5 H) 1.28 (s, 9 H) 461.9 135-AW

(DMSO-d₆) δ ppm 11.45 (s, 1 H) 8.66 (d, J = 8.34 Hz, 1 H) 8.31 (dd, J =9.09, 3.03 Hz, 1 H) 8.18 (d, J = 3.79 Hz, 1 H) 7.51 (d, J = 2.53 Hz, 1H) 7.19 (dd, J = 8.97, 2.40 Hz, 1 H) 7.04 (s, 1 H) 6.79 (t, J = 3.28 Hz,1 H) 5.15 (s, 1 H) 5.07 (s, 1 H) 4.66 (d, J = 3.28 Hz, 2 H) 1.80-2.10(m, 1 H) 1.44-1.70 (m, 4 H) 0.71- 0.95 (m, 4 H) 539.9 135-AX

(DMSO-d₆) δ ppm 11.46 (s, 1 H) 8.66 (d, J = 6.82 Hz, 1 H) 8.31 (dd, J =8.97, 1.89 Hz, 1 H) 8.18 (d, J = 3.79 Hz, 1 H) 7.50 (t, J = 2.27 Hz, 1H) 7.19 (dt, J = 9.09, 2.27 Hz, 1 H) 7.05 (s, 1 H) 6.79 (dd, J = 3.28,1.77 Hz, 1 H) 5.03 (s, 1 H) 4.95 (s, 1 H) 4.65 (d, J = 6.32 Hz, 2 H)2.75-2.92 (m, 1 H) 1.46-1.68 (m, 4 H) 1.01-1.22 (m, 6 H) 541.9 135-AY

(DMSO-d₆) δ ppm 11.24 (s, 1 H) 8.66 (d, J = 5.05 Hz, 1 H) 8.30 (d, J =8.84 Hz, 1 H) 8.31 (d, J = 9.09 Hz, 1 H) 8.18 (d, J = 3.79 Hz, 1 H) 7.50(d, J = 5.81 Hz, 1 H) 7.16-7.20 (m, 1 H) 6.78 (d, J = 5.56 Hz, 1 H) 6.71(d, J = 1.26 Hz, 1 H) 4.97 (s, 1 H) 4.90 (s, 1 H) 4.64 (d, J = 1.52 Hz,2 H) 2.11 (d, J = 6.57 Hz, 3 H) 419.1 135-AZ^(a)

(DMSO-d₆) δ ppm 11.28 (s, 1 H) 8.49 (br. S.) 8.46 (br. S.) 8.13-8.17 (m)8.12 (br. S.) 7.10 (d, J = 8.84 Hz, 1 H) 6.88 (d, J = 3.79 Hz, 1 H) 6.70(s, 1 H) 5.20 (br. S.) 5.16 (br. S.) 5.11 (br. S.) 4.80 (br. S.) 4.75(br. S.) 4.57-4.63 (m) 4.55 (br. S.) 4.50 (br. S.) 4.05 (d, J = 19.45Hz, 1 H) 3.05-3.18 (m) 2.82- 2.91 (m) 2.21 (s, 3 H) 2.18 (s, 2 H) 2.13(s, 1 H) 1.29 (d, J = 7.07 Hz, 6 H) 1.21 (d, J = 6.82 Hz, 2 H) 1.08 (d,J = 6.82 Hz, 1 H) 489.2 135-BA^(b)

(DMSO-d₆) δ ppm 11.25 (s, 1 H) 8.49 (br. S.) 8.46 (br. S.) 8.13-8.16 (m)8.12 (s, 1 H) 7.10 (d, J = 9.09 Hz, 1 H) 6.87 (d, J = 3.79 Hz, 1 H) 6.68(s, 1 H) 5.17-5.24 (m) 5.16 (br. S.) 5.11 (br. S.) 4.80 (br. S.) 4.75(br. S.) 4.56-4.64 (m) 4.54 (br. S.) 4.50 (br. S.) 4.08 (br. S.) 4.03(br. S.) 3.13-3.18 (m) 3.07- 3.13 (m) 2.85-2.91 (m) 2.84 (br. S.) 2.21(s, 3 H) 2.18 (s, 2 H) 2.13 (s, 1 H) 1.21 (d, J = 6.82 Hz, 2 H)1.13-1.18 (m, 2 H) 1.08 (d, J = 6.82 Hz, 1 H) 0.91- 0.97 (m, 2 H) 501.2135-BB

(DMSO-d₆) δ ppm 11.45 (s, 1 H) 8.66 (d, J = 5.05 Hz, 1 H) 8.31 (dd, J =8.97, 2.15 Hz, 1 H) 8.17 (d, J = 3.79 Hz, 1 H) 7.51 (t, J = 2.91 Hz, 1H) 7.19 (ddd, J = 8.97, 4.55, 2.40 Hz, 1 H) 7.04 (s, 1 H) 6.79 (dd, J =4.04, 1.52 Hz, 1 H) 4.97 (s, 1 H) 4.90 (s, 1 H) 4.64 (s, 2 H) 2.11 (d, J= 6.57 Hz, 3 H) 1.54-1.60 (m, 4 H) 513.1 135-BC^(a)

(DMSO-d₆) δ ppm 11.42 (s, 1 H) 8.48 (br. S.) 8.46 (br. S.) 8.13-8.16 (m)8.12 (br. S.) 7.10 (d, J = 8.84 Hz, 1 H) 7.04 (s, 1 H) 6.88 (d, J = 3.79Hz, 1 H) 5.17-5.23 (m) 5.16 (br. S.) 5.11 (br. S.) 4.80 (br. S.) 4.75(br. S.) 4.57-4.64 (m) 4.54 (br. S.) 4.50 (br. S.) 4.07 (br. S.) 4.02(br. S.) 3.15 (br. S.) 3.12 (m) 2.82-2.91 (m) 2.21 (s, 1 H) 2.17 (s, 1H) 2.12 (s, 1 H) 1.52-1.59 (m, 2 H) 1.21 (d, J = 7.07 Hz, 1 H) 1.08 (d,J = 7.33 Hz, 1 H) 555.1 135-BD

(DMSO-d₆) δ ppm 11.23 (br. S., 1 H) 8.62 (d, J = 6.06 Hz, 1 H) 8.03-8.25(m, 2 H) 7.12 (dd, J = 8.97, 6.19 Hz, 1 H) 6.88 (d, J = 3.79 Hz, 1 H)6.67 (s, 1 H) 4.82-5.09 (m, 2 H) 4.64 (s, 2 H) 2.26 (d, J = 4.04 Hz, 3H) 2.11 (d, J = 8.59 Hz, 3 H) 1.46 (s, 3 H) 1.08-1.24 (m, 2 H) 0.87-1.01(m, 2 H) 473.2 135-BE^(a)

(DMSO-d₆) ppm 11.24 (s, 1 H) 8.48 (br. S.) 8.46 (br. S.) 8.12-8.17 (m)8.11 (s, 1 H) 7.09 (d, J = 8.84 Hz, 1 H) 6.87 (d, J = 3.79 Hz, 1 H) 6.66(s, 1 H) 5.16-5.24 (m) 5.15 (br. S.) 5.11 (br. S.) 4.80 (br. S.) 4.75(br. S.) 4.58 (d, 1 H) 4.54 (br. S.) 4.50 (br. S.) 3.99-4.10 (m) 3.16(br. S.) 3.12 (br. S.) 2.19- 2.24 (m, 3 H) 2.15-2.19 (m, 2 H) 2.12 (br.S.) 1.18-1.25 (m, 2 H) 1.05-1.11 (m, 3 H) 0.92-0.97 (m, 2 H) 487.2135-BF

(DMSO-d₆) ppm 11.44 (s, 1 H) 8.62 (d, J = 6.06 Hz, 1 H) 8.04-8.26 (m, 2H) 7.12 (dd, J = 8.84, 5.81 Hz, 1 H) 7.04 (s, 1 H) 6.90 (d, J = 3.79 Hz,1 H) 4.84- 5.07 (m, 2 H) 4.64 (s, 2 H) 2.26 (d, J = 3.79 Hz, 3 H) 2.11(d, J = 8.59 Hz, 3 H) 1.44-1.63 (m, 4 H) 527.2 135-BG

(DMSO-d₆) ppm 11.22 (s, 1 H) 8.62 (d, J = 6.06 Hz, 1 H) 8.02-8.25 (m, 2H) 7.11 (dd, J = 8.72, 5.94 Hz, 1 H) 6.88 (d, J = 3.79 Hz, 1 H) 6.65 (s,1 H) 4.84- 5.08 (m, 2 H) 4.64 (s, 2 H) 2.26 (d, J = 3.79 Hz, 3 H)2.15-2.20 (m, 1 H) 2.11 (d, J = 8.59 Hz, 3 H) 1.06-1.12 (m, 2 H)0.92-0.97 (m, 2 H) 459.2 135-BH^(a)

(DMSO-d₆) δ ppm 11.22 (s, 1 H), 8.50 (br. S., 1 H), 8.28 (d, J = 9.6 Hz,1 H), 8.15 (d, J = 3.8 Hz, 1 H), 7.46 (d, J = 2.5 Hz, 1 H), 7.14 (dd, J= 9.0, 2.5 Hz, 1 H), 6.75 (d, J = 4.4 Hz, 1 H), 6.65 (s, 1 H), 5.07-5.30(m, 0 H), 4.78 (d, J = 22.1 Hz, 0 H), 4.64 (br. S., 0 H), 4.49 (d, J =18.9 Hz, 0 H), 4.06 (d, J = 18.6 Hz, 0 H), 2.99-3.14 (m, 0 H), 2.78-2.89(m, 0 H), 2.10-2.25 (m, 1 H), 1.16- 1.26 (m, 0 H), 0.99-1.12 (m, 0 H),0.90-0.98 (m, 0 H) 487.1 135-BI^(a)

(DMSO-d₆) δ ppm 11.13 (br. S., 1 H), 8.50 (br. S., 1 H), 8.30 (d, J =9.0 Hz, 1 H), 8.15 (d, J = 3.8 Hz, 1 H), 7.45 (d, J = 2.4 Hz, 1 H), 7.13(dd, J = 8.9, 2.3 Hz, 1 H), 6.73 (d, J = 3.8 Hz, 1 H), 6.65 (s, 1 H),5.19-5.25 (m), 5.11-5.18 (m), 4.79 (d, J = 18.6 Hz), 4.59-4.70 (m),4.44-4.53 (m), 4.01-4.09 (m), 3.00- 3.12 (m), 2.78-2.88 (m), 2.36-2.48(m), 2.12-2.21 (m, 1 H), 1.47-1.64 (m, 2 H), 1.20 (d, J = 5.6 Hz, 2 H),1.03- 1.11 (m), 0.90-0.97 (m) 501.1 135-BJ^(a)

(DMSO-d₆) δ ppm 11.08 (s, 1 H) 8.48-8.55 (m, 1 H) 8.30 (d, J = 9.09 Hz,1 H) 8.18 (d, J = 3.79 Hz, 1 H) 7.46 (d, J = 2.27 Hz, 1 H) 7.13 (d, J =9.09 Hz, 1 H) 7.06 (s, 1 H) 6.75 (d, J = 3.79 Hz, 1 H) 5.10- 5.12 (m)4.74 (br. s.) 4.52-4.54 (m) 4.24 (d, J = 7.07 Hz) 4.01-4.10 (m) 3.10(br. s.) 2.85 (br. s.) 2.11-2.18 (m) 1.42 (t, J = 7.33 Hz) 1.20-1.22 (m)1.08-1.10 (m) 528.1 135-BK^(a)

(DMSO-d₆) δ ppm 10.54 (s, 1 H) 8.49- 8.53 (m, 1 H) 8.29 (d, J = 9.09 Hz,1 H) 8.18 (d, J = 3.54 Hz, 1 H) 7.43 (d, J = 2.53 Hz, 1 H) 7.10 (dd, J =8.97, 2.40 Hz, 1 H) 6.69 (d, J = 3.03 Hz, 1 H) 6.37 (s, 1 H) 5.15-5.35(m, 1 H) 4.05-4.58 (m, 2 H) 3.05-3.20 (m, 1 H) 2.79-2.86 (m, 1 H) 2.45(s, 3 H) 2.12-2.17 (m, 3 H) 1.59 (s, 9 H) 1.07-1.23 (m, 3 H) 502.1135-BL^(a)

(DMSO-d₆) δ ppm 11.04 (s, 1 H) 8.46- 8.56 (m, 1 H) 8.30 (d, J = 8.84 Hz,1 H) 8.17 (d, J = 3.79 Hz, 1 H) 7.46 (d, J = 2.27 Hz, 1 H) 7.14 (dd, J =9.09, 2.53 Hz, 1 H) 7.07 (s, 1 H) 6.75 (d, J = 3.79 Hz, 1 H) 5.13 (m)4.76 (m) 4.47-4.62 (m,) 4.06 (s) 3.99-4.04 (m) 3.95 (s, 3 H) 3.11 (br.S.) 3.05-3.09 (m) 2.85 (br. S.) 2.17 (br. S.) 2.12 (br. S.) 1.23-1.28(m) 1.17-1.23 (m) 1.10 (s) 514.2 135-BM^(a)

(DMSO-d₆) δ ppm 11.21 (s, 1 H) 8.47 (s, 1 H) 8.07-8.19 (m, 2 H) 7.10 (d,J = 9.09 Hz, 1 H) 6.87 (d, J = 3.03 Hz, 1 H) 6.65 (s, 1 H) 4.98-5.28 (m)4.49- 4.73 (m) 4.02-4.19 (m) 3.12 (br. s.) 2.90 (br. s.) 2.22 (s, 3 H)2.14-2.20 (m, 1 H) 1.23 (br. s.) 1.05-1.13 (m) 0.91- 0.98 (m) 0.82-0.89(m) 0.73-0.82 (m) 513.2 135-BN^(a)

(DMSO-d₆) δ 11.21 (s, 1 H) 8.46 (s, 1 H) 8.01-8.20 (m, 2 H) 7.09 (d, J =8.84 Hz, 1 H) 6.86 (d, J = 3.79 Hz, 1 H) 6.65 (s, 1 H) 4.67-4.88 (m)4.22-4.34 (m) 4.13 (qd, J = 7.07, 1.26 Hz, 2 H) 2.95- 3.07 (m) 2.78-2.92(m) 2.21 (s, 3 H) 1.24 (t, J = 7.07 Hz, 3 H) 1.15 (d, J = 7.07 Hz, 3 H)1.05-1.11 (m, 2 H) 0.92-0.97 (m, 2 H). 517.1 135-BO^(a)

(DMSO-d₆) δ 11.21 (s, 1 H) 8.46 (br. s., 1 H) 8.03-8.21 (m, 2 H) 7.09(d, J = 8.84 Hz, 1 H) 6.86 (d, J = 3.79 Hz, 1 H) 6.65 (s, 1 H) 5.08-5.27(m, 1 H) 4.80 (br. s.) 4.62 (br. s.) 4.42-4.53 (m) 3.99-4.14 (m)3.05-3.18 (m) 2.88 (br. s.) 2.21 (s, 3 H) 2.14-2.19 (m) 1.21 (br. s.)1.01-1.12 (m) 0.91-0.97 (m, 2 H) 501.2 135-BP^(a)

(DMSO-d₆) δ 11.03 (s, 1 H) 8.43-8.51 (m, 1 H) 8.08-8.19 (m, 2 H)7.03-7.12 (m, 2 H) 6.85 (d, J = 3.79 Hz, 1 H) 5.13 (m) 4.71-4.82 (m)4.59 (br. s.) 4.46- 4.56 (m) 4.00-4.11 (m) 3.95 (s, 3 H) 3.07-3.18 (m)2.81-2.92 (m) 2.21 (s, 3 H) 2.17 (s, 2 H) 2.12 (s, 1 H) 1.21 (d, J =6.57 Hz, 2 H) 1.08 (d, J = 6.57 Hz, 1 H) 528.2 135-BQ^(a)

(DMSO-d₆) δ 11.07 (s, 1 H) 8.42-8.51 (m, 1 H) 8.10-8.18 (m, 2 H)7.04-7.11 (m, 2 H) 6.85 (d, J = 3.54 Hz, 1 H) 5.13 (m) 4.75 (br. s.)4.54 (br. s) 4.24 (q, J = 7.07 Hz, 2 H) 4.05 (m) 2.81-2.92 (m) 2.21 (s,3 H) 2.17 (s) 2.12 (s) 1.42 (t, J = 7.20 Hz, 3 H) 1.22 (m) 1.08 (m) 542.21 ^(a1)H NMR spectra collected at 27° C. in DMSO-d₆ solution. Atthis temperature, the identified compounds exist as a mixture of amiderotamers (presumably due to hindered rotation around the nitrogencarbonyl bond). This does not permit for unequivocal assignment of eachproton NMR signal. For signals that include both rotamers, assignment ofshift, coupling, and proton number are noted. Other peaks correspondingto individual rotamers are noted by shift and coupling. ^(b1)H NMRspectra collected at the temperature listed with the Table for samplesin DMSO-d₆ solution. At the specified temperature, the rate of rotationabout the amide bond is sufficiently fast such that the ¹H NMR signalsfor the separate rotamers have collasced to a single signal therebypermiting assignment of each signal the proton NMR spectrum.

EXAMPLE 136 136-A.5-((S)-7-Ethyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-cyclopropyl-isoxazol-3-yl)-amide

Prepared with similar method to that described for Example 37. MS (ESI)m/z 459.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.21 (s, 1H), 8.42 (s,1H), 8.27 (d, J=9.1 Hz, 1H), 8.15 (d, J=3.5 Hz, 1H), 7.44 (d, J=2.3 Hz,1H), 7.13 (dd, J=8.8, 2.3 Hz, 1H), 6.75 (d, J=3.8 Hz, 1H), 6.65 (s, 1H),3.59-3.75 (m, 2H), 3.05-3.17 (m, 1H), 2.93 (dd, J=16.7, 5.3 Hz, 1H),2.67-2.77 (m, 1H), 2.53-2.64 (m, 2H), 2.11-2.23 (m, 1H), 1.04-1.12 (m,8H), 0.91-0.98 (m, 2H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 136-B

  5-((S)-7-Ethyl-6-methyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3- yl]-amide (DMSO-d₆) δ ppm 11.45(br. S., 1 H), 8.42 (s, 1 H), 8.29 (d, J = 9.0 Hz, 1 H), 8.15 (d, J =3.8 Hz, 1 H), 7.45 (d, J = 2.3 Hz, 1 H), 7.14 (dd, J = 9.0, 2.4 Hz, 1H), 7.05 (s, 1 H), 6.76 (d, J = 3.7 Hz, 1 H), 3.66 (s, 2 H), 3.06-3.16(m, 1 H), 2.93 (dd, J = 17.0, 4.7 Hz, 1 H), 2.65-2.77 (m, 1 H),2.53-2.63 (m, 2 H), 1.52- 1.59 (m, 5 H), 1.03-1.12 (m, 5 H) 527.2 136-C

  5-((S)-7-Ethyl-6-methyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid [5-(1-methyl-cyclopropyl)-1H-pyrazol-3-yl]- amide (DMSO-d₆) δ ppm 12.12 (s, 1H), 10.55 (s, 1 H), 8.42 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.16 (d, J= 3.8 Hz, 1 H), 7.42 (d, J = 2.3 Hz, 1 H), 7.09 (dd, J = 9.0, 2.4 Hz, 1H), 6.70 (d, J = 3.8 Hz, 1 H), 6.30 (d, J = 2.3 Hz, 1 H), 3.66 (s, 2 H),3.03- 3.19 (m, 1 H), 2.86-2.98 (m, 1 H), 2.65-2.78 (m, 1 H), 2.52-2.65(m, 2 H), 1.41 (s, 3 H), 1.02-1.13 (m, 6 H), 0.89-0.96 (m, 2 H),0.74-0.81 (m, 2 H) 472.2 136-D

  5-((S)-7-Ethyl-6-methyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert- butyl-isoxazol-3-yl)-amide(DMSO-d₆) δ ppm 11.26 (br. S., 1 H), 8.42 (s, 1 H), 8.35 (d, J = 8.8 Hz,1 H), 8.13 (d, J = 3.8 Hz, 1 H), 7.41 (d, J = 2.3 Hz, 1 H), 7.08 (dd, J= 9.0, 2.1 Hz, 1 H), 6.67-6.71 (m, 1 H), 6.66 (s, 1 H), 3.56 (s, 2 H),2.81-2.87 (m, 2 H), 2.72- 2.79 (m, 2 H), 2.58 (q, J = 7.1 Hz, 2 H), 1.33(s, 9 H), 1.12 (t, J = 7.2 Hz, 3 H). 461.2 136-E

  5-((S)-7-Isopropyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4- yloxy)-indole-1-carboxylic acid (5-cyclopropyl-isoxazol-3-yl)-amide (DMSO-d₆) δ ppm 11.21 (br. S, 1 H) 8.41(s, 1 H) 8.27 (d, J = 9.09 Hz, 1 H) 8.15 (d, J = 3.79 Hz, 1 H) 7.44 (d,J = 2.27 Hz, 1 H) 7.13 (dd, J = 8.97, 2.40 Hz, 1 H) 6.75 (d, J = 3.28Hz, 1 H) 6.65 (s, 1 H) 3.60-3.81 (m, 2 H) 3.07-3.25 (m, 2 H) 2.91 (dd, J= 17.94, 2.53 Hz, 1 H) 2.09-2.24 (m, 1 H) 1.11-1.18 (m, 6 H) 1.05-1.11(m, 3 H) 1.02 (d, J = 6.06 Hz, 3 H) 0.90-0.97 (m, 2 H) 473.1 136-F

  5-((S)-7-Ethyl-6-methyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (4,4-dimethyl-4,5,6,7-tetrahydro-pyrazolo[l,5- a]pyridine-2-yl)-amide(DMSO-d₆) δ ppm 10.62 (s, 1 H), 8.42 (s, 1 H), 8.29 (d, J = 9.1 Hz, 1H), 8.15 (d, J = 3.8 Hz, 1 H), 7.42 (d, J = 2.3 Hz, 1 H), 7.09 (dd, J =9.0, 2.4 Hz, 1 H), 6.70 (d, J = 3.5 Hz, 1 H), 6.40 (s, 1 H), 3.96 (t, J= 6.2 Hz, 2 H), 3.57-3.71 (m, 2 H), 3.05-3.17 (m, 1 H), 2.92 (dd, J =17.1, 4.7 Hz, 1 H), 2.65-2.78 (m, 1 H), 2.51- 2.65 (m, 2 H), 1.92-2.09(m, 1 H), 1.57-1.74 (m, 1 H), 1.30 (s, 6 H), 1.10 (d, 3 H), 1.08 (t, 3H) 500.1 136-G

  5-(7-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-tert-butyl-isoxazol-3-yl)-amide (DMSO-d₆) δ ppm 11.25 (br. S., 1 H),8.42 (s, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 8.16 (d, J = 3.8 Hz, 1 H),7.44 (d, J = 2.0 Hz, 1 H), 7.13 (dd, J = 8.8, 2.3 Hz, 1 H), 6.74 (d, J =3.5 Hz, 1 H), 6.68 (s, 1 H), 3.51 (s, 2 H), 2.84 (t, J = 5.4 Hz, 2 H),2.71 (t, J = 5.7 Hz, 2 H), 2.41 (s, 3 H), 1.34 (s, 9 H) 447.2 136-H

  5-((S)-6-Methyl-7-propyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (5- cyclopropyl-isoxazol-3-yl)-amide(DMSO-d₆) δ ppm 11.21 (s, 1 H) 8.42 (s, 1 H) 8.28 (d, J = 9.09 Hz, 1 H)8.15 (d, J = 3.79 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.12 (dd, J =8.97, 2.40 Hz, 1 H) 6.74 (d, J = 3.54 Hz, 1 H) 6.65 (s, 1 H) 3.66 (d, J= 5.05 Hz, 2 H) 3.06-3.17 (m, 1 H) 2.92 (dd, J = 17.05, 4.67 Hz, 1 H)2.53-2.62 (m, 2 H) 2.11-2.23 (m, 1 H) 1.43-1.61 (m, 2 H) 1.01-1.13 (m, 5H) 0.82-0.98 (m, 6 H) (d, J = 6.06 Hz, 3 H) 0.90-0.97 (m, 2 H) 473.1136-I

  5-((S)-7-Ethyl-6-methyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-2-yl)-amide (DMSO-d₆) δppm 10.62 (s, 1 H), 8.42 (s, 1 H), 8.27 (d, J = 9.1 Hz, 1 H), 8.14 (d, J= 3.8 Hz, 1 H), 7.42 (d, J = 2.3 Hz, 1 H), 7.10 (dd, J = 9.0, 2.4 Hz, 1H), 6.70 (d, J = 3.5 Hz, 1 H), 6.27 (s, 1 H), 4.09 (t, J = 6.9 Hz, 1 H),3.66 (br. S., 2 H), 3.06- 3.17 (m, 1 H), 2.92 (dd, J = 17.2, 4.8 Hz, 1H), 2.65-2.77 (m, 1 H), 2.52-2.64 (m, 2 H), 2.29-2.38 (m, 3 H), 1.32 (s,6 H), 1.09 (overlapping d, J = 6.8 Hz, 3 H), 1.06 (overlapping t, J =6.8 Hz, 3 H). 486.1 136-J

  5-((S)-6,7-Dimethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1- carboxylic acid(5-cyclopropyl-isoxazol-3- yl)-amide (DMSO-d₆) δ ppm 11.24 (s, 1 H),8.42 (s, 1 H), 8.27 (d, J = 9.0 Hz, 1 H), 8.15 (d, J = 3.7 Hz, 1 H),7.45 (d, J = 2.3 Hz, 1 H), 7.13 (dd, J = 9.0, 2.4 Hz, 1 H), 6.75 (d, J =3.8 Hz, 1 H), 6.66 (s, 1 H), 3.75 (d, J = 17.6 Hz, 1 H), 3.48 (d, J =17.6 Hz, 1 H), 2.91 (dd, J = 16.9, 4.0 Hz, 1 H), 2.72 (dq, J = 12.5, 6.4Hz, 1 H), 2.55 (d, J = 8.0 Hz, 1 H), 2.36 (s, 3 H), 2.11- 2.24 (m, 1H),1.16 (d, J = 6.3 Hz, 3 H), 1.03-1.12 (m, 2 H), 0.91-0.99 (m, 2 H) 445.1136-K

  5-((S)-7-Cyclopropylmethyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin- 4-yloxy)-indole-1-carboxylicacid [5-(1- trifluoromethyl-cyclopropyl)-isoxazol-3- yl]-amide (DMSO-d₆)δ ppm 11.43 (s, 1 H) 8.42 (s, 1 H) 8.28 (d, J = 9.09 Hz, 1 H) 8.15 (d, J= 3.79 Hz, 1 H) 7.45 (d, J = 2.53 Hz, 1 H) 7.14 (dd, J = 8.84, 2.27 Hz,1 H) 7.04 (s, 1 H) 6.77 (d, J = 3.54 Hz, 1 H) 3.73-3.84 (m, 2 H)3.17-3.23 (m, 1 H) 2.94 (dd, J = 17.43, 5.31 Hz, 1 H) 2.54-2.63 (m, 1 H)2.43-2.47 (m, 2 H) 1.54-1.59 (m, 4 H) 1.07 (d, J = 6.57 Hz, 3 H)0.86-0.93 (m, 1 H) 0.51 (d, J = 8.34 Hz, 2 H) 0.13-0.17 (m, 2 H) 553.2136-L

  5-(7-Ethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid(5-cyclopropyl-isoxazol-3-yl)-amide (DMSO-d₆) δ ppm 11.21 (s, 1 H), 8.42(s, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 8.15 (d, J = 3.8 Hz, 1 H), 7.44 (d,J = 2.3 Hz, 1 H), 7.13 (dd, J = 9.0, 2.4 Hz, 1 H), 6.75 (d, J = 3.8 Hz,1 H), 6.65 (s, 1 H), 3.57 (s, 2 H), 2.71-2.90 (m, 4 H), 2.59 (q, J = 7.1Hz, 2 H), 2.10-2.22 (m, 1 H), 1.02-1.19 (m, 5 H), 0.86-0.98 (m, 2H),445.2

EXAMPLE 137 137-A.1-[5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone

To a solution of 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole (12g, 36.2 mmol) in THF (300 mL), NaH (1.74 g, 43.5 mmol) and aceticanhydride (5.13 mL, 54.3 mmol) are added. After 1 h the reaction isquenched with aqueous ammonium chloride and extracted with EtOAc. Mostof the impurities are removed passing it through a silica gel columneluting with 50:50 heptane:EtOAc to give crude1-[5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone. This isthen dissolved in TFA (300 mL) and heated to 100° C. for 6 hours. Atthis point the solvent is removed and1-[5-(6-hydroxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone isolatedvia FCC eluting with EtOAc. MS (ESI) m/z 284.0 (M+1).

137-B. [6-(1H-Indol-5-yloxy)-pyrimidin-4-ylmethyl]-methyl-carbamic acidtert-butyl ester

To a solution of1-[5-(6-hydroxymethyl-pyrimidin-4-yloxy)-indol-1-yl]-ethanone (7.92 g,28.0 mmol) in DCM (300 mL), MsCl (3.27 mL, 41.9 mmol) and triethylamine(7.79 mL, 55.9 mmol) are added followed by DMAP (0.342 g, 2.80 mmol). Atthis point the reaction is stirred for 1 h at 0° C. Water is then addedand the reaction extracted with EtOAc. To a solution of the concentratedproduct (11.2 g, 31.0 mmol) in THF (1000 mL), methylamine (2 M in THF)(465 mL, 930 mmol) is added and the reaction stirred for 24 h. At thispoint the solvent is removed and the residue is then re-dissolved in DCM(300 mL) and Boc-anhydride (8.64 mL, 37.2 mmol) is added. After 10 h thesolvent is evaporated and the residue separated using FCC eluting withHeptane:EtOAc 100:0 to 50:50 to give the title compound. MS (ESI) m/z355.1 (M+1).

137-C. 5-(6-Methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-isopropyl-1H-pyrazol-3-yl)-amide

[6-(1H-Indol-5-yloxy)-pyrimidin-4-ylmethyl]-methyl-carbamic acidtert-butyl ester (300 mg, 0.846 mmol) is dissolved in DMF (8.46 mL),cooled to 0° C. and flushed with nitrogen. NaH (102 mg, 2.54 mmol) isadded. The reaction is stirred in the ice bath for 30 minutes beforeExample 5-F (439 mg, 1.270 mmol) is added in 6 mL of DMF. After 2 h thereaction is cooled in an ice bath and diluted with 15 mL of ethylacetate and quenched with 2 mL of a saturated solution of ammoniumchloride. The mixture is diluted with ethyl acetate and placed in aseparatory funnel. The organic layer is removed and the water layer isextracted with another 50 mL ethyl acetate. The combined organics aredried, and concentrated. The solid is dissolved in 10 mL of DCM, cooledto 0° C., and treated with 2 mL of TFA. The ice bath is removed after 30minutes and after an additional 1 h the reaction is concentrated andthen diluted with 10 mL of ethyl acetate. The solution is treated with 3mL of ammonium hydroxide. The solution is concentrated again to a whitesolid. The solid absorbed onto silica and separated via flashchromatography (0-10% NH₃/MeOH:DCM) to obtain the title compound. MS(ESI) m/z 406.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.22 (br. S.,1H) 10.59 (br. S., 1H) 8.65 (d, J=1.01 Hz, 1H) 8.32 (d, J=9.09 Hz, 1H)8.18 (d, J=3.79 Hz, 1H) 7.45 (d, J=2.53 Hz, 1H) 7.11 (dd, J=8.84, 2.53Hz, 1H) 7.03 (d, J=1.01 Hz, 1H) 6.72 (d, J=3.28 Hz, 1H) 6.34 (s, 1H)3.71 (s, 2H) 2.96 (t, J=7.07 Hz, 1H) 2.29 (s, 3H) 1.25 (d, J=6.82 Hz,6H).

The following compounds are prepared with similar method or by similarmethod to those described for Example 19, Example 112-D, and/or Example76-D.

137-D

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(4,4- dimethyl-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-2-yl)-amide(DMSO-d₆) δ ppm 10.64 (br. S., 1 H), 8.65 (s, 1 H), 8.30 (d, J = 8.8 Hz,1 H), 8.16 (d, J = 3.5 Hz, 1 H), 7.45 (d, J = 2.3 Hz, 1 H), 7.12 (dd, J= 8.8, 2.5 Hz, 1 H), 7.03 (s, 1 H), 6.72 (d, J = 3.5 Hz, 1 H), 6.27 (s,1 H), 4.04-4.14 (m, 2 H), 3.70 (s, 2 H), 2.31-2.38 (m, 2 H), 2.29 (s, 3H), 1.32 (s, 6 H) 432.1 137-E

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid[5-(1- methyl cyclopropyl)-isoxazol-3-yl]-amide (DMSO-d₆) δ ppm 8.66 (d,J = 1.01 Hz, 1 H) 8.32 (d, J = 9.09 Hz, 1 H) 8.17 (d, J = 3.79 Hz, 1 H)7.47 (d, J = 2.53 Hz, 1 H) 7.14 (dd, J = 8.84, 2.27 Hz, 1 H) 7.04 (d, J= 1.01 Hz, 1 H) 6.76 (d, J = 3.79 Hz, 1 H) 6.67 (s, 1 H) 3.73 (s, 2 H)2.29 (s, 3 H) 1.46 (s, 3 H) 1.12-1.14 (m, 2 H) 0.84-1.00 (m, 2 H) 419.0137-F

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(5- cyclopropyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 12.24 (br. S., 1H) 10.56 (br. S., 1 H) 8.65 (d, J = 1.01 Hz, 1 H) 8.31 (d, J = 9.09 Hz,1 H) 8.17 (d, J = 3.79 Hz, 1 H) 7.44 (d, J = 2.02 Hz, 1 H) 7.11 (d, J =9.09 Hz, 1 H) 7.03 (d, J = 1.01 Hz, 1 H) 6.71 (d, J = 3.54 Hz, 1 H) 6.22(s, 1 H) 3.71 (s, 2 H) 2.29 (s, 3 H) 1.88-1.95 (m, 1 H) 0.84-0.99 (m, 2H) 0.72 (dd, J = 4.80, 2.02 Hz, 2 H) 404.1 137-G

  5-(6-Dimethylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(5- isopropyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 12.22 (br. S., 1 H)10.59 (s, 1 H) 8.67 (d, J = 1.01 Hz, 1 H) 8.32 (d, J = 9.09 Hz, 1 H)8.19 (d, J = 3.54 Hz, 1 H) 7.46 (d, J = 2.53 Hz, 1 H) 7.11- 7.14 (m, 1H) 6.97 (d, J = 1.01 Hz, 1 H) 6.72 (d, J = 3.54 Hz, 1 H) 6.34 (s, 1 H)3.51 (s, 2 H) 2.21 (s, 6 H) 2.19 (d, J = 4.04 Hz, 1 H) 1.25 (d, J = 6.82Hz, 6 H) 420.1 137-H

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(1-tert- butyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 10.73 (br. S., 1H) 8.65 (d, J = 1.01 Hz, 1 H) 8.32 (d, J = 8.84 Hz, 1 H) 8.22 (d, J =3.54 Hz, 1 H) 7.78 (d, J = 2.53 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H)7.10-7.12 (m, 1 H) 7.03 (d, J = 1.01 Hz, 1 H) 6.71 (d, J = 3.03 Hz, 1 H)6.52 (d, J = 2.27 Hz, 1 H) 3.70 (s, 2 H) 2.28 (s, 3 H) 1.54 (s, 9 H)420.1 137-I

  5-(6-Cyclopropylaminomethyl-pyrimidin- 4-yloxy)-indole-1-carboxylicacid (5- isopropyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 12.22 (br. S.,1 H), 10.59 (br. S., 1 H), 8.65 (d, J = 1.0 Hz, 1 H), 8.26-8.41 (m, 1H), 8.17 (br. S., 1 H), 7.42 (br. S., 1 H), 7.06-7.13 (m, 1 H), 7.04 (s,1 H), 6.70 (br. S., 1 H), 6.26- 6.41 (m, 1 H), 3.79 (s, 2 H), 2.86- 3.04(m, 1 H), 2.04-2.16 (m, 1 H), 1.24 (d, J = 6.6 Hz, 6 H), 0.30-0.40 (m, 2H), 0.21-0.27 (m, 2 H) 432.1 137-J

  5-(6-Ethylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid (5-isopropyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 12.22 (br. S., 1 H)10.58 (s, 1 H) 8.66 (d, J = 1.01 Hz, 1 H) 8.32 (d, J = 9.09 Hz, 1 H)8.18 (d, J = 3.79 Hz, 1 H) 7.45 (d, J = 2.53 Hz, 1 H) 7.07 (d, J = 1.01Hz, 1 H) 7.11 (dd, J = 8.84, 2.53 Hz, 1 H) 6.72 (d, J = 3.54 Hz, 1 H)6.34 (s, 1 H) 3.79 (s, 2 H) 2.97 (d, J = 6.57 Hz, 1 H) 2.57-2.59 (m, 2H) 1.25 (d, J = 7.07 Hz, 6 H) 1.03 (t, J = 7.07 Hz, 3 H) 420.1 137-K

  5-(6-Propylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(5- isopropyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 12.22 (br. S., 1 H)10.58 (s, 1 H) 8.64 (d, J = 1.01 Hz, 1 H) 8.32 (d, J = 8.84 Hz, 1 H)8.18 (d, J = 3.79 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.11- 7.12 (m, 1H) 7.06 (d, J = 1.01 Hz, 1 H) 6.71 (d, J = 3.28 Hz, 1 H) 6.34 (d, J =1.26 Hz, 1 H) 3.74 (s, 2 H) 2.95 (d, J = 7.07 Hz, 1 H) 1.40-1.43 (m, 2H) 1.25 (d, J = 7.07 Hz, 6 H) 1.22 (br. S., 1 H) 0.81- 0.88 (m, 4 H)434.2 137-L

  5-[6-(Isopropylamino-methyl)-pyrimidin- 4-yloxy]-indole-1-carboxylicacid (5- isopropyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 12.21 (br. S.,1 H) 10.58 (s, 1 H) 8.65 (s, 1 H) 8.32 (d, J = 8.84 Hz, 1 H) 8.18 (d, J= 3.79 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.04-7.12 (m, 1 H) 7.11 (d, J= 8.84 Hz, 1 H) 6.72 (d, J = 3.54 Hz, 1 H) 6.34 (s, 1 H) 3.79 (s, 2 H)2.94-2.99 (m, 1 H) 2.73-2.76 (m, 1 H) 1.25 (d, J = 6.82 Hz, 6 H) 1.00(d, J = 6.32 Hz, 6 H) 434.2 137-M

  5-(6-Cyclobutylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylicacid (5- isopropyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 12.21 (br. S.,1 H) 10.58 (s, 1 H) 8.64 (d, J = 1.01 Hz, 1 H) 8.32 (d, J = 8.84 Hz, 1H) 8.18 (d, J = 3.54 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.09- 7.12 (m,1 H) 7.05 (d, J = 1.01 Hz, 1 H) 6.72 (d, J = 3.54 Hz, 1 H) 6.34 (s, 1 H)3.68 (s, 2 H) 3.17 (d, J = 5.31 Hz, 1 H) 2.95 (d, J = 6.57 Hz, 1 H)2.02-2.09 (m, 2 H) 1.51-1.72 (m, 4 H) 1.25 (d, J = 7.07 Hz, 6 H) 446.2137-N

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(5- cyclopropyl-1-methyl-1H-pyrazol-3-yl)- amide (DMSO-d₆) δ ppm 8.65(d, J = 1.01 Hz, 1 H) 8.30 (d, J = 9.09 Hz 1 H) 8.16 (d, J = 3.79 Hz, 1H) 7.44 (d, J = 2.02 Hz, 1 H) 7.11 (dd, J = 8.84, 2.27 Hz, 1 H) 7.02 (d,J = 1.01 Hz, 1 H) 6.71 (d, J = 3.03 Hz, 1 H) 6.16 (s, 1 H) 3.79 (s, 3 H)3.70 (s, 2 H) 2.28 (s, 3 H) 1.81-1.99 (m, 1 H) 0.96-0.99 (m, 2 H)0.59-0.73 (m, 2 H) 418.1 137-O

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(1-methyl- 5-trifluoromethyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 8.66(d, J = 1.01 Hz, 1 H) 8.32 (d, J = 9.09 Hz, 1 H) 8.18 (d, J = 3.79 Hz, 1H) 7.47 (d, J = 2.53 Hz, 1 H) 7.13 (d, J = 2.53 Hz, 1 H) 7.04 (d, J =1.01 Hz, 1 H) 7.07 (s, 1 H) 6.76 (d, J = 3.79 Hz, 1 H) 3.95 (s, 3 H)3.72 (s, 2 H) 2.29 (s, 3 H) 446.1 137-P

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid[5- methyl-1-(2,2,2-trifluoro-ethyl)-1H- pyrazol-3-yl]-amide (DMSO-d₆) δppm 8.65 (d, J = 1.01 Hz, 1 H) 8.31 (d, J = 8.84 Hz, 1 H) 8.20 (d, J =3.79 Hz, 1 H) 7.45 (d, J = 2.53 Hz, 1 H) 7.11-7.13 (m, 1 H) 7.03 (d, J =1.01 Hz, 1 H) 6.72 (d, J = 4.29 Hz, 1 H) 6.51 (s, 1 H) 4.97-5.05 (m, 2H) 3.71 (s, 2 H) 2.26-2.35 (m, 6 H) 460.1 137-Q

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(5- isopropyl-isoxazol-3-yl)-amide (DMSO-d₆) δ ppm 8.66 (d, J = 1.01 Hz,1 H) 8.32 (d, J = 9.09 Hz, 1 H) 8.17 (d, J = 3.79 Hz, 1 H) 7.47 (d, J =2.53 Hz, 1 H) 7.14 (dd, J = 8.97, 2.40 Hz, 1 H) 7.04 (s, 1 H) 6.76 (d, J= 3.79 Hz, 1 H) 6.69 (s, 1 H) 3.73 (s, 2 H) 3.07-3.14 (m, 1 H) 2.30 (s,3 H) 1.28-1.31 (m, 6 H) 407.1 137-R

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(5- cyclopropyl-isoxazol-3-yl)-amide (DMSO-d₆) δ ppm 8.66 (s, 1 H) 8.32(d, J = 9.09 Hz, 1 H) 8.16 (d, J = 3.79 Hz, 1 H) 7.46 (d, J = 2.53 Hz, 1H) 7.13 (dd, J = 8.97, 2.40 Hz, 1 H) 7.04 (s, 1 H) 6.74 (d, J = 3.79 Hz,1 H) 6.65 (s, 1 H) 3.71 (s, 2 H) 2.29 (s, 3 H) 2.13-2.20 (m, 1 H) 1.08(dd, J = 8.46, 2.65 Hz, 2 H) 0.94 (dd, J = 4.80, 2.53 Hz, 2 H) 405.1137-S

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid[5- (1-trifluoromethyl-cyclopropyl)-1H- pyrazol-3-yl]-amide (DMSO-d₆) δppm 12.79 (br. S., 1 H) 8.66 (s, 1 H) 8.32 (d, J = 8.84 Hz, 1 H) 8.18(br. S., 1 H) 7.46 (d, J = 2.27 Hz, 1 H) 7.12 (dd, J = 8.97, 2.40 Hz, 1H) 7.04 (s, 1 H) 6.73 (d, J = 3.28 Hz, 1 H) 6.67 (br. S., 1 H) 3.72 (s,2 H) 2.30 (s, 3 H) 1.40 (br. S., 2 H) 1.29 (br. S., 2 H) 472.2 137-T

  5-{6-[(2-Methoxy-ethylamino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylic acid(5-cyclopropyl-isoxazol-3-yl)- amide (DMSO-d₆) δ ppm 8.65 (d, J = 1.01Hz, 1 H) 8.30 (d, J = 9.09 Hz, 1 H) 8.17 (d, J = 3.54 Hz, 1 H) 7.47 (d,J = 2.27 Hz, 1 H) 7.14 (dd, J = 8.97, 2.40 Hz, 1 H) 7.07 (s, 1 H) 6.76(d, J = 3.79 Hz, 1 H) 6.65 (s, 1 H) 3.78 (s, 2 H) 3.38 (t, J = 5.56 Hz,2 H) 3.22 (s, 3 H) 2.68 (t, J = 5.68 Hz, 2 H) 2.14-2.21 (m, 1 H)1.06-1.11 (m, 2 H) 0.92-0.97 (m, 2 H) 449.0 137-U

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(1, 5-dimethyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 8.65 (d, J = 1.01Hz, 1 H) 8.31 (d, J = 9.09 Hz, 1 H) 8.17 (d, J = 3.79 Hz, 1 H) 7.44 (d,J = 2.02 Hz, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1 H) 7.02 (d, J = 1.01Hz, 1 H) 6.72 (d, J = 3.03 Hz, 1 H) 6.34 (s, 1 H) 3.67-3.71 (m, 5 H)2.27-2.30 (m, 6 H) 392.2 137-V

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid[5- (4-methyl-tetrahydro-pyran-4-yl)- isoxazol-3-yl]-amide (DMSO-d₆) δppm 8.66 (d, J = 1.01 Hz, 1 H) 8.33 (d, J = 9.09 Hz, 1 H) 8.18 (d, J =3.79 Hz, 1 H) 7.47 (d, J = 2.53 Hz, 1 H) 7.14 (dd, J = 8.97, 2.40 Hz, 1H) 7.05 (s, 1 H) 6.75-6.78 (m, 2 H) 6.30-6.31 (m, 1 H) 3.71-3.77 (m, 4H) 3.46 (ddd, J = 11.75, 8.59, 2.91 Hz, 2 H) 2.30 (s, 3 H) 2.05 (d, J =9.85 Hz, 2 H) 1.64-1.71 (m, 2 H) 1.34 (s, 3 H) 463.2 137-W

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid[5- (1-methyl-cyclopropyl)-1H-pyrazol-3-yl]- amide (DMSO-d₆) δ ppm 12.13(s, 1 H) 10.57 (br. S., 1 H) 8.65 (d, J = 1.01 Hz, 1 H) 8.32 (d, J =9.09 Hz, 1 H) 8.18 (d, J = 3.54 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.11(dd, J = 8.97, 2.40 Hz, 1 H) 7.03 (d, J = 1.01 Hz, 1 H) 6.71 (d, J =3.79 Hz, 1 H) 6.30 (d, J = 2.02 Hz, 1 H) 3.71 (s, 2 H) 2.29 (s, 3 H)1.41 (s, 3 H) 0.91- 0.95 (m, 2 H) 0.76-0.80 (m, 2 H). 418.2 137-X

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(1- isopropyl-5-methyl-1H-pyrazol-3-yl)- amide (DMSO-d₆) δ ppm 10.64 (s,1 H) 8.65 (d, J = 1.01 Hz, 1 H) 8.31 (d, J = 8.84 Hz, 1 H) 8.20 (d, J =3.79 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1H) 7.02 (s, 1 H) 6.70 (d, J = 3.79 Hz, 1 H) 6.33 (s, 1 H) 4.37-4.58 (m,1 H) 3.70 (s, 2 H) 2.29 (d, J = 3.54 Hz, 6 H) 1.38 (d, J = 6.57 Hz, 6 H)420.2 137-Y

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid[5- (1-trifluoromethyl-cyclopropyl)-isoxazol- 3-yl]-amide (DMSO-d₆) δppm 8.67 (s, 1 H) 8.35 (d, J = 9.09 Hz, 1 H) 8.16 (d, J = 3.54 Hz, 1 H)7.46 (d, J = 2.27 Hz, 1 H) 7.13 (dd, J = 8.97, 2.40 Hz, 1 H) 7.04 (d, J= 5.31 Hz, 2 H) 6.74 (d, J = 3.79 Hz, 1 H) 3.77 (s, 2 H) 2.30-2.34 (m, 3H) 1.50-1.59 (m, 4 H) 473.2 137-Z

  5-(6-Aminomethyl-pyrimidin-4-yloxy)- indole-1-carboxylic acid[5-(1-tri fluoromethyl-cyclopropyl)-isoxazol-3-yl]- amide (DMSO-d₆) δppm 8.67 (s, 1 H) 8.39 (d, J = 8.84 Hz, 1 H) 8.15 (d, J = 3.54 Hz, 1 H)7.43 (d, J = 2.53 Hz, 1 H) 7.07-7.13 (m, 2 H) 7.03 (s, 1 H) 6.71 (d, J =3.79 Hz, 1 H) 3.85 (s, 2 H) 1.49-1.57 (m, 4 H) 459.1 137-AA

  5-(6-Methylaminomethyl-pyrimidin- 4 yloxy)-indole-1-carboxylic acid(5- cyclopropyl-1-ethyl-1H-pyrazol-3-yl)- amide (DMSO-d₆) δ ppm 10.64(br. s., 1 H) 8.65 (s, 1 H) 8.30 (d, J = 9.09 Hz, 1 H) 8.17 (d, J = 3.79Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.11 (dd, J = 8.97, 2.40 Hz, 1 H)7.03 (d, J = 1.01 Hz, 1 H) 6.71 (d, J = 4.29 Hz, 1 H) 6.16 (s, 1 H) 4.15(q, J = 7.24 Hz, 2 H) 3.72 (s, 2 H) 2.30 (s, 3 H) 1.83- 1.98 (m, 1H)1.32-1.43 (m, 3 H) 0.93- 1.04 (m, 2 H) 0.60-0.73 (m, 2 H) 432.2 137-AB

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(1,5- dicyclopropyl-1H-pyrazol-3-yl)-amide (DMSO-d₆) δ ppm 10.64 (br.s., 1 H) 8.65 (d, J = 1.01 Hz, 1 H) 8.30 (d, J = 8.84 Hz, 1 H) 8.16 (d,J = 3.79 Hz, 1 H) 7.44 (d, J = 2.53 Hz, 1 H) 7.10 (dd, J = 8.84, 2.53Hz, 1 H) 7.02 (s, 1 H) 6.70 (d, J = 3.79 Hz, 1 H) 6.16 (s, 1 H) 3.70 (s,2 H) 3.57-3.63 (m, 1 H) 2.28 (s, 3 H) 2.03-2.10 (m, 1 H) 0.99-1.12 (m, 6H) 0.69-0.74 (m, 2 H) 444.2 137-AC

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(5- cyclopropyl-1-isopropyl-1H-pyrazol- 3-yl)-amide (DMSO-d₆) δ ppm10.66 (br. s., 1 H) 8.66 (s, 1 H) 8.31 (d, J = 8.84 Hz, 1 H) 8.19 (d, J= 3.54 Hz, 1 H) 7.44 (d, J = 2.27 Hz, 1 H) 7.10 (dd, J = 8.97, 2.40 Hz,1 H) 7.03 (s, 1 H) 6.70 (d, J = 3.03 Hz, 1 H) 6.17 (s, 1 H) 4.76 (quin,J = 6.57 Hz, 1 H) 3.73 (s, 2 H) 2.30 (s, 3 H) 1.86-2.00 (m, 1 H) 1.42(d, J = 6.57 Hz, 6 H) 0.91- 1.04 (m, 2 H) 0.60-0.72 (m, 2 H) 446.2137-AD

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid[1- methyl-5-(1-trifluoromethyl-cyclopropyl)- 1H-pyrazol-3-yl]-amide(DMSO-d₆) δ ppm 8.65 (d, J = 1.26 Hz, 1 H) 8.31 (d, J = 8.84 Hz, 1 H)8.17 (d, J = 3.54 Hz, 1 H) 7.45 (d, J = 2.27 Hz, 1 H) 7.12 (dd, J =8.97, 2.40 Hz, 1 H) 7.03 (d, J = 1.01 Hz, 1 H) 6.73 (d, J = 3.03 Hz, 1H) 6.66 (s, 1 H) 3.83 (s, 3 H) 3.70 (s, 2 H) 2.29 (s, 3 H) 1.49-1.52 (m,2 H) 1.30-1.34 (m, 2 H) 486.2 137-AE

  5-(6-Methylaminomethyl-pyrimidin-4- yloxy)-indole-1-carboxylic acid(5- isopropyl-1-methyl-1H-pyrazol-3-yl)- amide (DMSO-d₆) δ ppm 10.62(br. s., 1 H) 8.66 (d, J = 1.01 Hz, 1 H) 8.32 (d, J = 8.84 Hz, 1 H) 8.17(d, J = 3.54 Hz, 1 H) 7.45 (d, J = 2.02 Hz, 1 H) 7.11 (dd, J = 8.97,2.40 Hz, 1 H) 7.03 (d, J = 1.01 Hz, 1 H) 6.72 (d, J = 3.03 Hz, 1 H) 6.36(s, 1 H) 3.72 (s, 5 H) 3.04 (dt, J = 13.64, 6.82 Hz, 1 H) 2.22-2.38 (m,3 H) 1.23 (d, J = 6.82 Hz, 6 H) 420.2

EXAMPLE 138 138-A.5-(6-Methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid(4,4-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-amide

Prepared by similar method to that described in Example 86A. MS (ESI)m/z 481.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1H), 8.77 (s,1H), 8.31 (d, J=8.8 Hz, 1H), 8.16 (d, J=3.5 Hz, 1H), 7.49 (d, J=2.3 Hz,1H), 7.19 (s, 1H), 7.15 (dd, J=9.0, 2.4 Hz, 1H), 6.73 (d, J=3.8 Hz, 1H),6.28 (s, 1H), 4.69 (s, 2H), 4.09 (t, J=6.9 Hz, 2H), 3.11 (s, 3H),2.29-2.38 (m, 2H), 1.32 (s, 6H).

The following compounds are prepared by similar method.

138-B. 5-(6-Methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylicacid (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-amide

MS (ESI) m/z 453.0 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H),8.78 (d, J=1.0 Hz, 1H), 8.32 (d, J=9.1 Hz, 1H), 8.17 (d, J=3.8 Hz, 1H),7.48 (d, J=2.5 Hz, 1H), 7.18 (d, J=1.0 Hz, 1H), 7.14 (dd, J=9.0, 2.4 Hz,1H), 6.73 (d, J=3.8 Hz, 1H), 6.28 (s, 1H), 4.69 (s, 2H), 4.04 (t, J=7.1Hz, 2H), 3.11 (s, 3H), 2.88 (t, J=7.2 Hz, 2H).

EXAMPLE 139 139-A.5-(7-Methanesulfonyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-cyclopropyl-isoxazol-3-yl)-amide

Prepared by similar method to that described in Example 35. MS (ESI) m/z495.1 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.22 (s, 1H), 8.50 (s,1H), 8.28 (d, J=9.1 Hz, 1H), 8.16 (d, J=3.8 Hz, 1H), 7.47 (d, J=2.3 Hz,1H), 7.15 (dd, J=8.8, 2.3 Hz, 1H), 6.76 (d, J=3.8 Hz, 1H), 6.65 (s, 1H),4.39 (s, 2 H), 3.57 (t, J=5.8 Hz, 2H), 3.06 (s, 3H), 2.96 (t, J=5.7 Hz,2H), 2.12-2.25 (m, 1H), 1.04-1.13 (m, 2 H), 0.89-0.99 (m, 2H).

The following compounds are prepared by similar method.

139-B.5-(7-Methanesulfonyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-tert-butyl-isoxazol-3-yl)-amide

MS (ESI) m/z 511.2 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.27 (s, 1H),8.51 (s, 1H), 8.29 (d, J=9.0 Hz, 1H), 8.17 (d, J=3.7 Hz, 1H), 7.47 (d,J=2.4 Hz, 1H), 7.16 (dd, J=9.0, 2.3 Hz, 1H), 6.77 (d, J=3.7 Hz, 1H),6.68 (s, 1H), 4.39 (s, 2H), 3.57 (t, J=5.9 Hz, 2H), 3.06 (s, 3H), 2.96(t, 2H), 1.34 (s, 9H).

139-C.5-((S)-7-Methanesulfonyl-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-cyclopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 509.1 (M+1); 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.22 (s, 1H),8.51 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 8.16 (d, J=3.8 Hz, 1H), 7.47 (d,J=2.3 Hz, 1H), 7.16 (dd, J=9.0, 2.4 Hz, 1H), 6.76 (d, J=3.8 Hz, 1H),6.65 (s, 1H), 4.29-4.63 (m, 3H), 3.06 (s, 4H), 2.80 (d, J=16.9 Hz, 1H),2.10-2.27 (m, 1H), 1.23 (d, J=6.8 Hz, 3H), 1.03-1.14 (m, 2H), 0.89-0.99(m, 2H).

139-D.5-(6-Methanesulfonyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide

MS (ESI) m/z 549.15 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.45 (s, 1H)8.67 (s, 1H) 8.31 (d, J=8.84 Hz, 1H) 8.17 (d, J=4.04 Hz, 1H) 7.50 (d,J=2.78 Hz, 1H) 7.18 (dd, J=8.97, 2.40 Hz, 1H) 7.04 (s, 1H) 6.79 (d,J=4.04 Hz, 1H) 4.71-4.77 (m, 4H) 3.10 (s, 3H) 1.54-1.60 (m, 4H).

EXAMPLE 140 140-A.5-0)-6-Methyl-7-methylcarbamoylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid (5-cyclopropyl-isoxazol-3-yl)-amide

Prepared by similar method to that described in Example 41-C. MS (ESI)m/z 502.1 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.22 (s, 1H) 8.43 (s,1H) 8.28 (d, J=8.84 Hz, 1H) 8.15 (d, J=3.79 Hz, 1H) 7.82 (d, J=4.55 Hz,1H) 7.44 (d, J=2.27 Hz, 1H) 7.12 (dd, J=8.84, 2.27 Hz, 1H) 6.75 (d,J=3.79 Hz, 1H) 6.65 (s, 1H) 3.74 (d, J=4.55 Hz, 2H) 3.08-3.22 (m, 3H)3.00 (dd, J=17.05, 4.67 Hz, 1H) 2.59-2.66 (m, 4H) 2.09-2.24 (m, 1H)1.03-1.15 (m, 5H) 0.89-1.00 (m, 2H).

The following compounds are prepared by similar method.

140-B.5-((S)-6-Methyl-7-methylcarbamoylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-methyl-cyclopropyl)-1H-pyrazol-3-yl]amide

MS (ESI) m/z 501.3 (M+1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.13 (s, 1H),10.56 (s, 1H), 8.43 (s, 1H), 8.30 (d, J=9.1 Hz, 1H), 8.17 (d, J=3.5 Hz,1H), 7.83 (d, J=4.3 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.08 (dd, J=9.0,2.4 Hz, 1H), 6.71 (d, J=3.5 Hz, 1H), 6.29 (s, 1H), 3.68 (s, 2H), 3.19(s, 2H), 2.87 (dd, J=15.8, 4.7 Hz, 4H), 2.64 (d, J=4.5 Hz, 3H), 1.41 (s,3H), 0.89-0.96 (m, 2H), 0.72-0.82 (m, 2H).

EXAMPLE 141(S)-4-[1-(5-Cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylicacid ethylamide

Prepared with similar method to that described for Example 36 usingethyl isocyanate. MS (ESI) m/z 502.1 (M+1); rotamers exist at 27° C. inDMSO-d₆, 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.22 (s, 1H) 8.49 (s, 1H) 8.28(d, J=9.09 Hz, 1H) 8.15 (d, J=3.79 Hz, 1H) 7.46 (d, J=2.27 Hz, 1H) 7.15(dd, J=8.97, 2.40 Hz, 1H) 6.75 (d, J=3.28 Hz, 1H) 6.69 (t, J=5.18 Hz,1H) 6.65 (s, 1H) 4.68-4.85 (m, 2H) 4.14 (d, J=18.95 Hz, 1H) 3.11 (ddd,J=7.26, 5.12, 2.53 Hz, 2H) 2.88-2.99 (m, 1H) 2.72-2.82 (m, 1H) 2.12-2.23(m, 1H) 1.02-1.13 (m, 8H) 0.89-0.99 (m, 2H).

EXAMPLE 142 142-A. 1-Hydroxymethyl-cyclopropanecarboxylic acid methylester

A solution of cyclopropane-1,1-dicarboxylic acid methyl ester (9 g, 62.4mmol) in THF (180 mL), is cooled to 0° C. and triethylamine (9.7 mL,69.6 mmol) and 3-methyl-butyryl chloride (9.1 mL, 9.6 mmol) are addedand the reaction stirred for 1 h. In a separate flask, sodiumborohydride (7.1 g, 188 mmol) is dissolved in THF (100 mL)/H₂O (25 mL)and cooled to 0° C. The mixed anhydride is filtered through a sinteredfunnel to remove salts from previous reaction and added to the flaskcontaining sodium borohydride and the reaction stirred for 1 h at 0° C.1 N HCl is added and the product is extracted with EtOAc and then withCCl₃H/iPrOH. It is then purified via FCC eluting with Heptane/EtOAc(100:0 to 20:80) to give 1-hydroxymethyl-cyclopropanecarboxylic acidmethyl ester. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.61 (t, J=5.81 Hz, 1H)3.59 (s, 3H) 3.55 (d, J=6.06 Hz, 2H) 1.01 (d, J=3.03 Hz, 2H) 1.01 (d,J=10.36 Hz, 1H) 0.87 (d, J=3.03 Hz, 1H) 0.85-0.88 (m, 1H).

142-B. 3-(1-Hydroxymethyl-cyclopropyl)-3-oxo-propionitrile

To a solution of LDA (115 mmol) in THF (300 mL), at −78° C., a solutionof 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (5 g, 28.4mmol) in CH3CN (5.91 mL, 115 mmol) is added. The reaction is allowed toreach rt. At this point it is quenched with 1N HCl (200 mL) andextracted with EtOAc (200 mL, ×3). It is then dried and evaporated togive 3-(1-hydroxymethyl-cyclopropyl)-3-oxo-propionitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.26 (s, 2H) 4.03 (s, 1H) 3.58 (br. s., 2H)1.15-1.16 (m, 2H) 0.92-0.95 (m, 2H).

142-C. [1-(3-Amino-isoxazol-5-yl)-cyclopropyl]-methanol

Prepared with similar method to that described above in Example 7-A. MS(ESI) m/z 155.2 (M+1).

142-D.{5-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-isoxazol-3-yl}-carbamicacid phenyl ester

To a solution of [1-(3-amino-isoxazol-5-yl)-cyclopropyl]-methanol (3.6g, 23.35 mmol) in DCM (200 mL) at 0° C., imidazole (2.385 g, 35.0 mmol)and tert-butylchlorodimethylsilane (4.22 g, 28.0 mmol) are added. After1 h the reaction is complete. After washing the organics with 1N HCl theorganics are concentrated and then dissolved in THF (200 mL) at 0° C.,and pyridine (3.62 ml, 44.7 mmol) and phenyl chloroformate (5.63 mL,44.7 mmol) are added. After 1 h the reaction is complete and it isquenched with water. The organics are then extracted with EtOAc, driedand evaporated. The title compound is then isolated using FCC andelution with heptane:EtOAc 100:0 to 90:10. MS (ESI) m/z 389.0 (M+1).

142-E.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-yl]-amide

To a solution of tert-butyl4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (2 g,5.68 mmol) in DMF (50 mL), at 0° C., NaH (0.681 g, 17.0 mmol) and{5-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-isoxazol-3-yl}-carbamicacid phenyl ester (3.09 g, 7.95 mmol) are added. After 1 h the reactionis complete. After quenching with water, the organics are extracted withEtOAc and the fractions combined, dried and evaporated. The crudeproduct is dissolved in THF (10 mL) at 0° C. and TBAF (17.0 ml, 17.03mmol) is added. After 2 h at it the reaction is complete and is quenchedwith NH₄Cl and extracted with EtOAc. The product is separated with FCCeluting with 50:50 heptane:EtOAc to give4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester which is then dissolved in DCM (10 mL) and TFA (10mL) is added. The reaction is stirred for 20 minutes. The organics arethen evaporated and the crude product is taken up in EtOAc and NH₄OH(37% in water) is added to free-base the amine. Then the flask is againsubjected to vacuum to remove the excess EtOAc. The crude product isthen loaded onto a silica gel column and eluted with DCM:MeOH:NH₄OH100:0:0 to 90:9.5:0.5 to give the title compound. MS (ESI) m/z 433.9(M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.25 (s, 1H) 8.65 (d, J=2.02 Hz,1H) 8.31 (d, J=8.84 Hz, 1H) 8.18 (d, J=3.79 Hz, 1H) 7.50 (d, J=2.53 Hz,1H) 7.18 (dd, J=9.09, 2.27 Hz, 1H) 6.80-6.82 (m, 2H) 4.99 (s, 1H)4.58-4.67 (m, 4H) 3.66 (d, J=5.81 Hz, 2H) 1.10-1.11 (m, 2H) 1.03-1.04(m, 2H).

EXAMPLE 143 143-A.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-aminomethyl-cyclopropyl)-isoxazol-3-yl]-amide

To a solution of4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-a]pyrimidine-6-carboxylicacid tert-butyl ester (500 mg, 0.939 mmol) in THF (10 mL), at 0° C.,triethylamine (0.262 mL, 1.88 mmol) methanesulfonyl chloride (0.110 mL,1.41 mmol) and DMAP (11.5 mg, 0.094 mmol) are added. After 2 h thereaction is complete and is quenched with water and the organicsextracted with EtOAc. The crude product following concentration is thendissolved in THF (30 mL), and NH₃ in MeOH (1.82 mL, 12.8 mmol) is added.The reaction is stirred for 36 h. At this point the volatiles areremoved and the crude product is dissolved in DCM (10 mL) and then TFA(10 mL, 130 mmol) is added. After 10 minutes the volatiles are removedin vacuo. The product is dissolved in EtOAc and then NH₄OH is added. Theorganics are removed and the crude product separated via FCC elutingwith DCM:MeOH:NH₄OH (100:0:0 to 92:7:1) to give the title compound. MS(ESI) m/z 432.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (s, 1H) 8.35(d, J=8.84 Hz, 1H) 8.15 (d, J=3.54 Hz, 1H) 7.44 (d, J=2.53 Hz, 1H) 7.11(dd, J=9.09, 2.53 Hz, 1H) 6.77 (s, 1H) 6.70 (d, J=4.04 Hz, 1H) 4.09 (d,J=11.87 Hz, 4H) 2.94 (s, 2H) 1.05 (d, J=3.03 Hz, 4H).

EXAMPLE 144 144-A.4-{1-[5-(1-Formyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester

To a solution of SO3 pyridine (0.992 g, 6.23 mmol), triethylamine (1.086mL, 7.79 mmol) and DMSO (1.11 mL, 15.6 mmol) at 0° C.,4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester (0.83 g, 1.559 mmol) in DCM (5 mL) and DMSO (1 mL)is added. The reaction is stirred at 0° C. for 2 h. After the reactionis complete, it is quenched with NH₄CL, extracted, and evaporated.4-{1-[5-(1-Formyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylicacid tert-butyl ester is then obtained using FCC and eluting with 100:0heptane:EtOAc to 0:100 Heptane:EtOAc. MS (ESI) m/z 531.0 (M+1).

144-B.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-dimethylaminomethyl-cyclopropyl)-isoxazol-3-yl]-amide

To a solution of4-{1-[5-(1-formyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-a]pyrimidine-6-carboxylicacid tert-butyl ester (120 mg, 0.226 mmol) in DCE (2 ml), dimethylamine(0.34 mL, 0.679 mmol) and sodium triacetoxyborohydride (192 mg, 0.905mmol) are added. After 2 h the reaction is complete, brine is added andthe product is extracted with EtOAc. The organics are dried andevaporated to give the crude product. The mixture is diluted with DCM(10 mL) and then TFA (10 ml, 130 mmol) is added. After 10 minutes thevolatiles are removed in vacuo. The product is dissolved in EtOAc andthen NH₄OH is added. The organics are removed and the crude productseparated via FCC eluting with DCM:MeOH:NH₄OH (100:0:0 to 92:7:1) togive5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-dimethylaminomethyl-cyclopropyl)-isoxazol-3-yl]-amide. MS(ESI) m/z 460.9 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (s, 1H) 8.29(d, J=8.84 Hz, 1H) 8.16 (d, J=3.79 Hz, 1H) 7.47 (d, J=2.27 Hz, 1H) 7.16(s, 1H) 6.82 (s, 1H) 6.75 (d, J=4.04 Hz, 1H) 4.06-4.15 (m, 1H) 2.57 (s,2 H) 2.20 (s, 6H) 1.17 (d, J=2.27 Hz, 2H) 0.93 (d, J=2.27 Hz, 2H).

The following compounds are prepared with similar method.

144-C.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid [5-(1-methylaminomethyl-cyclopropyl)-isoxazol-3-yl]-amide

MS (ESI) m/z 446.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (s, 1H)8.32 (d, J=9.09 Hz, 1H) 8.16 (d, J=3.79 Hz, 1H) 7.46 (d, J=2.53 Hz, 1H)7.13-7.14 (m, 1H) 6.78 (s, 1H) 6.73 (d, J=3.79 Hz, 1H) 4.08-4.10 (m, 4H)2.84 (s, 2H) 2.33 (s, 3H) 1.05-1.18 (m, 2H) 1.00-1.01 (m, 2H).

144-D.5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylicacid(5-{1-[(2-methoxy-ethylamino)-methyl]-cyclopropyl}-isoxazol-3-yl)-amide

MS (ESI) m/z 490.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (s, 1H)8.30 (d, J=9.09 Hz, 1H) 8.16 (d, J=3.79 Hz, 1H) 7.46 (d, J=2.27 Hz, 1H)7.13-7.16 (m, 1H) 6.75 (d, J=3.79 Hz, 1H) 6.78 (s, 1H) 4.10 (d, J=15.16Hz, 4H) 3.37-3.39 (m, 2H) 3.25 (s, 3H) 2.88 (s, 2H) 2.70-2.72 (m, 2H)1.07-1.10 (m, 2H) 0.98-1.00 (m, 2H).

EXAMPLE 145 145-A.5-[6-(2-Methylamino-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid[5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide

Prepared with similar method to that described for Example 73-D MS (ESI)m/z 432.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.64 (d, J=1.01 Hz, 1H)8.36 (d, J=8.84 Hz, 1H) 8.15 (d, J=3.79 Hz, 1H) 7.43 (d, J=2.53 Hz, 1H)7.09-7.11 (m, 1H) 6.97 (s, 1H) 6.66 (s, 1H) 6.71 (d, J=3.79 Hz, 1H)2.84-2.89 (m, 4H) 2.32 (s, 3H) 1.45 (s, 3H) 1.13-1.15 (m, 2H) 0.90-0.92(m, 2H).

The following compounds are prepared with similar method.

145-B.5-[6-(2-Dimethylamino-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid(5-isopropyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 434.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.24 (s, 1H)10.61 (s, 1H) 8.63 (d, J=1.01 Hz, 1H) 8.31 (d, J=8.84 Hz, 1H) 8.18 (d,J=3.79 Hz, 1H) 7.44 (d, J=2.27 Hz, 1H) 7.10 (dd, J=8.84, 2.53 Hz, 1H)7.02 (s, 1H) 6.71 (d, J=3.54 Hz, 1H) 6.34 (d, J=1.26 Hz, 1H) 2.90-3.01(m, 1H) 2.84 (t, J=7.07 Hz, 2H) 2.60-2.70 (m, 2H) 2.19 (s, 6H) 1.25 (d,J=7.07 Hz, 6H).

145-C. 5-[6-(2-Methylamino-ethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid (5-isopropyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 420.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.24 (br. s.,1H) 8.63 (d, J=1.26 Hz, 1H) 8.31 (d, J=9.09 Hz, 1H) 8.18 (d, J=3.79 Hz,1H) 7.43 (d, J=2.27 Hz, 1H) 7.10 (dd, J=8.97, 2.40 Hz, 1H) 6.97 (d,J=1.01 Hz, 1H) 6.71 (d, J=3.03 Hz, 1H) 6.34 (s, 1H) 2.89-3.01 (m, 1H)2.76-2.86 (m, 4H) 2.28 (s, 3H) 1.25 (d, J=7.07 Hz, 6H)

EXAMPLE 146 146-A.5-{6-[(Acetyl-methyl-amino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid [5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-amide

Prepared with similar method to that described for Example 21 MS (ESI)m/z 515.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.44 (s, 1H) 8.59-8.74(m, 1H) 8.30 (d, J=9.09 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 7.43-7.53 (m,1H) 7.10-7.21 (m, 1H) 7.04 (s, 1H) 6.92 (s, 1H) 6.78 (d, J=3.54 Hz, 1H)4.63 (s, 1H) 4.54 (s, 1H) 3.09 (s, 2H) 2.84 (s, 1H) 2.10 (s, 2H) 2.03(s, 1H) 1.48-1.65 (m, 4H).

146-B.5-{6-[(Acetyl-methyl-amino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid (5-isopropyl-isoxazol-3-yl)-amide

MS (ESI) m/z 449.19 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.27 (s, 1H)8.60-8.78 (m, 1H) 8.27-8.35 (m, 1H) 8.14-8.21 (m, 1H) 7.44-7.51 (m, 1H)7.14 (dd, J=8.84, 2.53 Hz, 1H) 6.90-6.97 (m, 1H) 6.77 (t, J=2.91 Hz, 1H)4.59-4.61 (m, 1H) 4.63 (s, 1H) 4.54 (s, 1H) 3.10-3.15 (m, 1H) 3.09 (s,2H) 2.84 (s, 1H) 2.10 (s, 2H) 2.03 (s, 1H) 1.26-1.33 (m, 6H).

146-C.5-{6-[2-(Acetyl-methyl-amino)-ethyl]-pyrimidin-4-yloxy}-indole-1-carboxylicacid (5-isopropyl-1H-pyrazol-3-yl)-amide

MS (ESI) m/z 462.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.22 (s, 1H)10.58 (s, 1H) 8.67 (dd, J=14.91, 1.01 Hz, 1H) 8.32 (d, J=8.84 Hz, 1H)8.18 (d, J=3.54 Hz, 1H) 7.43 (d, J=2.02 Hz, 1H) 7.03-7.16 (m, 1H) 6.96(s, 1H) 6.72 (d, J=3.54 Hz, 1H) 6.34 (s, 1H) 3.57-3.69 (m, 2H) 2.93-3.01(m, 2H) 2.93 (s, 2H-rotamer) 2.83-2.89 (m, 1H) 2.78 (s, 1H-rotamer) 1.93(d, J=7.33 Hz, 3H) 1.25 (d, J=7.07 Hz, 6H)

EXAMPLE 1475-[6-(2-Methoxy-ethoxymethyl)-pyrimidin-4-yloxy]-indole-1-carboxylicacid [5-(1-methyl-cyclopropyl)-isoxazol-3-yl]-amide

Prepared with similar method to that described for Example 20-A MS (ESI)m/z 464.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.25 (s, 1H) 8.68 (d,J=1.01 Hz, 1H) 8.31 (d, J=9.09 Hz, 1H) 8.18 (d, J=3.79 Hz, 1H) 7.49 (d,J=2.53 Hz, 1H) 7.16 (dd, J=8.97, 2.40 Hz, 1H) 7.00 (d, J=1.01 Hz, 1H)6.77 (d, J=3.79 Hz, 1H) 6.67 (s, 1H) 4.57 (s, 2H) 3.63-3.69 (m, 2H)3.46-3.52 (m, 2 H) 3.21 (s, 3H) 1.46 (s, 3H) 1.13-1.17 (m, 2H) 0.90-0.97(m, 2H).

EXAMPLE 148 148-A. 4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester

To a solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (5 g, 20.4 mmol) in DCM (100 mL),Dess-Martin periodinane (12.97 g, 30.6 mmol) is added. After completionof the reaction as judged by TLC the reaction is quenched with satNaHCO₃, washed with sat sodium thiosulfate and extracted with DCM. Theorganics are dried and evaporated and used crude in the next step.

148-B. B-1. 5-Oxo-piperidine-1,2,4-tricarboxylic acid 1-tert-butyl ester4-ethyl ester 2-methyl ester and B-24-Oxo-piperidine-1,2,5-tricarboxylic acid 1-tert-butyl ester 5-ethylester 2-methyl ester

To a solution of 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester (3.73 g, 15.3 mmol) in diethyl ether (50 mL), at 0°C., boron trifluoride etherate (2.14 ml, 16.9 mmol) followed by ethyldiazoacetate (2.39 mL, 23.0 mmol) are added. After stirring overnightthe reaction is quenched with water and extracted with EtOAc. The twoproducts are isolated (as inseparable mixtures) using FCC eluting withheptane:EtOAc 1:1. MS (ESI) m/z 328.1 (M−1).

148-C. (±)-C-1.4-Oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylicacid 7-tert-butyl ester 6-ethyl ester and (±)-C-2.4-Oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6,7-dicarboxylicacid 6-tert-butyl ester 7-ethyl ester

To a solution of 5-oxo-piperidine-1,2,4-tricarboxylic acid 1-tert-butylester 4-ethyl ester 2-methyl ester and4-oxo-piperidine-1,2,5-tricarboxylic acid 1-tert-butyl ester 5-ethylester 2-methyl ester (2.84 g, 8.62 mmol) in EtOH (20 mL), formamidineacetate (1.347 g, 12.93 mmol) and sodium ethoxide (6.99 g, 21.6 mmol)are added and the reaction heated at 90° C. After 3 h, 0.75 eq offormamidine acetate is added added. After completion of reaction asjudged by LCMS the reaction is evaporated, quenched with NH₄Cl andextracted with DCM. The products are purified using FCC eluting withheptane:EtOAc 1:2 and isolated as an inseperable mixture. MS (ESI) m/z324.1 (M+1)

148-D. (±)-D-1.4-Chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid7-tert-butyl ester 6-ethyl ester and (±)-D-2.4-chloro-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6,7-dicarboxylic acid6-tert-butyl ester 7-ethyl ester

To a solution of the mixture of4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylicacid 7-tert-butyl ester 6-ethyl ester and4-Oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6,7-dicarboxylicacid 6-tert-butyl ester 7-ethyl ester (1.5 g, 4.64 mmol) in DCE (25 mL),carbon tetrachloride (1.34 mL, 13.9 mmol) and triphenylphosphine (2.43g, 9.28 mmol) are added. The reaction is heated at reflux and aftercompletion of reaction as judged by LCMS. The solvents are removed andthe products are isolated using FCC eluting with heptane:EtOAc 80:20. Atthis point the two products are separated.4-Chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid7-tert-butyl ester 6-ethyl ester MS (ESI) m/z 342.1 (M+1) and4-chloro-7,8-dihydro-5H-pyrido[4,3-a]pyrimidine-6,7-dicarboxylic acid6-tert-butyl ester 7-ethyl ester MS (ESI) m/z 342.1 (M+1) are isolatedas an almost 4:1 ratio.

148-E.(±)-4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylicacid 7-tert-butyl ester 6-ethyl ester

To a solution of4-chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid7-tert-butyl ester 6-ethyl ester (1 g, 2.93 mmol) in CH₃CN (30 mL),5-hydroxy-indole (0.779 g, 5.85 mmol) and DBU (0.88 mL, 5.85 mmol) areadded. After heating at 60° C. for 5 h the reaction is evaporated andthe product isolated using FCC eluting with heptane:EtOAc 1:1. MS (ESI)m/z 439.1 (M+1).

148-F.(±)-4-[1-(5-Cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylicacid 7-tert-butyl ester 6-ethyl ester

Prepared by similar method to that described in Example 56-A. MS (ESI)m/z 589.1 (M+1)

148-G.(±)-4-[1-(5-Cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-6-carboxylicacid methylamide

To a solution of4-[1-(5-cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylicacid 7-tert-butyl ester 6-ethyl ester (110 mg, 0.196 mmol) inTHF/EtOH/H₂O (3:1:1 mL) LiOH (0.016 g, 0.392 mmol) is added and thereaction stirred until starting material is consumed. At this point thereaction is quenched with 1N HCl (2 mL) and extracted with EtOAc. Afterdrying and evaporation, the crude product is dissolved in DCM (3 mL) at0° C., oxalyl chloride (0.026 mL, 0.294 mmol) and DMF (2 drops) areadded. At this point Methylamine (2 M in THF) (0.49 mL, 0.981 mmol) isadded and the reaction stirred for 1 h at rt. After work up with waterand extraction with EtOAc the crude product is dissolved in DCM (2 mL)and TFA (1 mL) is added. After removing the solvent in vacuo, andbasifying with NH₄OH, the product is separated using FCC eluting withDCM:MeOH:NH₄OH 100:0:0 to 90:8:2. MS (ESI) m/z 474.1 (M+1). ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.21 (s, 1H) 8.43 (s, 1H) 8.21-8.33 (m, 1H) 8.15(d, J=3.79 Hz, 1H) 7.94 (d, J=5.81 Hz, 1H) 7.44 (d, J=2.27 Hz, 1H) 7.12(d, J=9.09 Hz, 1H) 6.75 (d, J=3.03 Hz, 1H) 6.65 (s, 1H) 3.91-4.15 (m,2H) 3.61 (br. s, 1H) 2.83-2.95 (m, 2H) 2.66 (d, J=4.80 Hz, 3H) 2.12-2.24(m, 1H) 1.03-1.17 (m, 2H) 0.94 (dd, J=4.80, 2.53 Hz, 2H).

EXAMPLE 149 149-A. (4-(1H-indol-5-yloxy)pyridin-2-yl)methanol

To a solution of (4-chloropyridin-2-yl)methanol (384 mg, 2.67 mmol) inDMF (12 mL) is added 1H-indol-5-ol (534 mg, 4.01 mmol), and cesiumcarbonate (1307 mg, 4.01 mmol). The reaction is sealed and heated to160° C. via microwave irradiation for 30 min. The reaction mixture isthen cooled to room temperature and diluted brine and DCM. The resultinglayers are separated and the aqueous layer is extracted three additionaltimes with DCM. The organic layers are combined dried over anhydrousNa₂SO₄, filtered, and concentrated. The resulting residue is purifiedvia FCC (0-100% EtOAc/heptane) to give the title compound. MS (ESI) m/z241.2 (M+1).

149-B. tert-butyl(4-(1H-indol-5-yloxy)pyridin-2-yl)methyl(methyl)carbamate

To a solution of (4-(1H-indol-5-yloxy)pyridin-2-yl)methanol (2 g, 8.32mmol) in THF (40 mL) is added triethylamine (3.48 ml, 24.97 mmol). Thereaction mixture is cooled to 0° C., and methanesulfonyl chloride (0.973mL, 12.49 mmol) is added dropwise. The reaction is stirred at 0° C. for45 min at which time the reaction is placed at room temperature and a40% solution of methylamine in water (7.21 mL, 83 mmol) is added. Thereaction is stirred for 30 min and then diluted with brine. Theresulting mixture is extracted twice with ethyl acetate. The combinedorganic layers are dried over anhydrous Na₂SO₄, filtered, andconcentrated. The resulting residue is then dissolved in DCM (50 mL) anddi-tert-butyl dicarbonate (2.0 g, 9.15 mmol) is added. The reaction ispermitted to stir for approximately 30 minutes at room temperature atwhich time it is diluted with saturated aqueous NaHCO₃. The resultingmixture is extracted twice with DCM. The organic layers are combineddried over anhydrous Na₂SO₄, filtered, and concentrated. The resultingresidue is purified via FCC (0-100% EtOAc/heptane) to give the titlecompound. MS (ESI) m/z 354.3 (M+1).

149-C. tert-butyl(4-(1-(5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyridin-2-yl)methyl(methyl)carbamate

To a solution of tert-butyl(4-(1H-indol-5-yloxy)pyridin-2-yl)methyl(methyl)carbamate (115 mg, 0.325mmol), in DMF (5 ml) is added phenyl5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamate (126 mg, 0.488 mmol),prepared as described in Example 5-N. The resulting mixture is placed at0° C. and sodium hydride (60% dispersion in oil; 39.0 mg, 0.98 mmol) isadded. The reaction is permitted to stir at 0° C. for 30 min at whichtime the reaction is quenched with saturated aqueous NH₄Cl. Theresulting mixture is diluted with brine and DCM. The resulting layersare separated and the aqueous layer is extracted twice with DCM. Theorganic layers are combined, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The resulting residue is purified via FCC (0-100%EtOAc/heptane) to give the title compound. MS (ESI) m/z 517.6 (M+1).

149-D.N-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-5-(2-((methylamino)methyl)pyridin-4-yloxy)-1H-indole-1-carboxamide

To a solution of tert-butyl(4-(1-(5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyridin-2-yl)methyl(methyl)carbamate(0.124 g, 0.240 mmol) in DCM (5 ml) is added TFA (2 ml, 0.240 mmol). Thereaction is stirred for approximately 30 minutes and then concentratedin vacuo to near dryness. The residue is dissolved in DCM, diluted withwater and neutralized via the addition of saturated aqueous NaHCO₃. Theresulting layers are then separated and the aqueous layer is extractedtwice with DCM. The organic layers are combined dried over anhydrousNa₂SO₄, filtered, and concentrated. The resulting residue is purifiedvia FCC (0-15% MeOH/DCM) to provide the title compound. MS (ESI) m/z417.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.64-0.70 (m, 2H) 0.96-1.02(m, 2H) 1.87-1.96 (m, 1H) 2.27 (s, 3H) 3.71 (s, 2H) 3.80 (s, 3H) 6.16(d, J=0.51 Hz, 1H) 6.73 (dd, J=3.79, 0.51 Hz, 1H) 6.80 (dd, J=5.56, 2.53Hz, 1H) 6.93 (d, J=2.02 Hz, 1H) 7.09 (dd, J=8.97, 2.40 Hz, 1H) 7.42 (d,J=2.27 Hz, 1H) 8.17 (d, J=3.54 Hz, 1H) 8.33 (d, J=8.84 Hz, 1H) 8.36 (d,J=5.81 Hz, 1H).

The following compounds are prepared with similar method.

MS (ESI) m/z Structure/Chemical Name ¹H NMR (400 MHz) (M + 1) 149-E

  N-(5-cyclopropyl-1H-pyrazol-3-yl)- 5-(2-((methylamino)methyl)pyridin-4-yloxy)-1H-indole-1-carboxamide (DMSO-d₆ with ~1% d-TFA) δ ppm0.73-0.83 (m, 2 H) 0.92-1.07 (m, 2 H) 1.88-2.02 (m, 1 H) 2.61 (s, 3 H)4.31 (s, 2 H) 6.21 (s, 1 H) 6.78 (d, J = 3.03 Hz, 1 H) 7.16 (dd, J =8.97, 2.40 Hz, 1 H) 7.20-7.27 (m, 2 H) 7.50 (d, J = 2.53 Hz, 1 H) 8.18(d, J = 3.79 Hz, 1 H) 8.40 (d, J = 9.09 Hz, 1 H) 8.58-8.75 (m, 1 H)403.3 149-F

  N-(1-methyl-5-(trifluoromethyl)-1H- pyrazol-3-yl)-5-(2-((methylamino)methyl)pyridin-4- yloxy)-1H-indole-1-carboxamide (DMSO-d₆)δ ppm 2.26 (s, 3 H) 3.70 (s, 2 H) 3.94 (s, 3 H) 6.75 (d, J = 3.79 Hz, 1H) 6.79 (dd, J = 5.56, 2.53 Hz, 1 H) 6.92 (d, J = 2.27 Hz, 1 H) 7.06 (s,1 H) 7.11 (dd, J = 8.84, 2.53 Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1 H) 8.18(d, J = 3.79 Hz, 1 H) 8.34 (d, J = 5.56 Hz, 1 H) 8.35 (d, J = 2.53 Hz, 1H) 445.2 149-G

  N-(5-tert-butylisoxazol-3-yl)-5-(2- ((methylamino)methyl)pyridin-4-yloxy)-1H-indole-1-carboxamide (DMSO-d₆) δ ppm 1.34 (s, 9 H), 2.29 (s, 3H), 3.74 (s, 2 H), 6.67 (s, 1 H), 6.74 (d, J = 3.3 Hz, 1 H), 6.81 (dd, J= 5.7, 2.4 Hz, 1 H), 6.94 (d, J = 2.3 Hz, 1 H), 7.10 (dd, J = 9.0, 2.4Hz, 1 H), 7.42 (d, J = 2.5 Hz, 1 H), 8.17 (d, J = 3.5 Hz, 1 H), 8.33-8.39 (m, 2 H) 420.2 149-H

  N-(5-cyclopropylisoxazol-3-yl)-5-(2- ((methylamino)methyl)pyridin-4-yloxy)-1H-indole-1-carboxamide (DMSO-d₆) δ ppm 0.88-0.98 (m, 2 H) 1.03-1.13 (m, 2 H) 2.11-2.22 (m, J = 8.53, 8.53, 5.05, 4.93 Hz, 1 H) 2.30 (s,3 H) 3.75 (s, 2 H) 6.65 (s, 1 H) 6.75 (d, J = 3.54 Hz, 1 H) 6.82 (dd, J= 5.56, 2.53 Hz, 1 H) 6.94 (d, J = 2.53 Hz, 1 H) 7.11 (dd, J = 8.97,2.40 Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1 H) 8.17 (d, J = 3.79 Hz, 1 H)8.33-8.40 (m, 2 H) 404.2

EXAMPLE 150 150-A. (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate

To a suspension of nano zinc metallic powder (Strem Chemicals; averageparticle size 75-125 nm) (1.34 g, 20.52 mmol) in DMF (8 ml) is added1,2-dibromoethane (0.19 mL, 2.2 mmol). The heterogeneous mixture isheated to 60° C. and then stirred for 10 min. The mixture is cooled toroom temperature and charged with chlorotrimethylsilane (0.24 mL, 1.8mmol). The reaction vessel is then sonicated in a room temperature waterbath for 30 min. The suspension is then left standing for ca. 30 min topermit the solid to settle and the supernatant is then removed viasyringe. DMF (8 ml) is then added, followed by bromomethyl acetate (1.00mL, 10.3 mmol). The reaction mixture is then stirred for 2 hr at roomtemperature. The suspension is then left standing for 1 hour to permitthe solid to settle. Next a separate flask is charged with5-(2-chloropyrimidin-4-yloxy)-1H-indole (450 mg, 1.83 mmol), prepared asdescribed in Example 73-A, DMF (3 mL) is then added to the5-(2-chloropyrimidin-4-yloxy)-1H-indole followed by Pd(dppf)Cl₂.CH₂Cl₂(230 mg, 0.28 mmol). To this solution is added a portion of thesupernatant (6 mL), from the flask containing the organozincate, viasyringe. The reaction is heated at 50° C. for 16 h then cooled to roomtemperature and diluted with DCM and saturated aqueous NH₄Cl. The layersare separated and the aqueous layer is extracted 2 additional times withDCM. The organic layers are combined dried over anhydrous Na₂SO₄,filtered, and concentrated. The resulting residue is purified via FCC(0-60% EtOAc/DCM) to provide the title compound. MS (ESI) m/z 284.0(M+1).

150-B. (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methanol

To a solution of (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate(0.51 g, 1.8 mmol) in MeOH (18 mL) at 0° C. is added solid K₂CO₃ (0.6 g,4.5 mmol). The reaction is stirred for 30 minutes at 0° C. and thenwarmed to room temperature and stirred for an additional 30 minutes. Thereaction mixture is then diluted with DCM and water and the layers areseparated. The aqueous layer is extracted 2 additional times with DCM.The organic layers are combined dried over anhydrous Na₂SO₄, filtered,and concentrated to afford the title compound. MS (ESI) m/z 242.1 (M+1).

150-C. tert-butyl(4-(1H-indol-5-yloxy)pyrimidin-2-yl)methyl(methyl)carbamate

To a solution of (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methanol (0.47 g,1.95 mmol) and triethylamine (0.815 ml, 5.84 mmol) in THF at 0° C. isadded methanesulfonyl chloride (0.228 mL, 2.92 mmol). The reaction isallowed to stir at 0° C. for 45 min at which time a 40% solution ofmethylamine in water (3.37 ml, 39.0 mmol) is added. The reaction isplaced at room temperature and stirred for 30 min. The reaction is thendiluted with brine and ethyl acetate. The layers are separated and theaqueous layer is extracted two additional times with ethyl acetate. Theorganic layers are combined, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The resulting residue is then diluted with DCM (15 mL), tothe resulting solution is added di-tert-butyl dicarbonate (0.42 g, 1.9mmol). The reaction is permitted to stir for approximately 30 minutes atroom temperature, at which time it is diluted with saturated aqueousNaHCO₃. The resulting mixture is extracted twice with DCM. The organiclayers are combined dried over anhydrous Na₂SO₄, filtered, andconcentrated. The resulting residue is purified via FCC (30-80% EtOAc(2.5% EtOH)/heptane) to give the title compound. MS (ESI) m/z 355.2(M+1).

150-D. tert-butyl(4-(1-(5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-2-yl)methyl(methyl)carbamate

To a solution of tert-butyl (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methyl(methyl)carbamate (35 mg, 0.099 mmol) in THF (2 ml) is addedphenyl 5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamate (29.5 mg, 0.109mmol), which is prepared as described in Example 5-S. The mixture is putat 0° C. and NaH (60% dispersion in oil; 11.85 mg, 0.296 mmol) is thenadded and the reaction is then stirred for 30 minutes. The reaction isthen quenched with 10% AcOH/MeOH (0.3 mL) and further diluted with DCMand saturated aqueous NaHCO₃. The resulting layers are then separatedand the aqueous layer is extracted two additional times with DCM. Theorganic layers are combined, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The resulting residue is purified via FCC (10-100% EtOAc(2.5% EtOH)/DCM) to give the title compound. MS (ESI) m/z 532.3 (M+1).

150-E.N-(5-cyclopropyl-1-ethyl-1H-pyrazol-3-yl)-5-(2-((methylamino)methyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide

To a solution of tert-butyl(4-(1-(5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-2-yl)methyl(methyl)carbamate(33 mg, 0.062 mmol) in DCM (2 mL) at 0° C. is added TFA (0.7 mL, 9.1mmol). The reaction is stirred for 30 minutes at 0° C. and is thenplaced at room temperature for an additional 20 minutes. The reactionmixture is then concentrated in vacuo to near dryness and then dilutedwith DCM and water. The mixture is neutralized by the addition ofsaturated aqueous NaHCO₃ and the resulting layers are separated. Theaqueous layer is extracted two additional times with DCM. The organiclayers are combined, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The resulting residue is purified via FCC (0-20%MeOH)/DCM) to give the title compound. MS (ESI) m/z 432.2 (M+1).(DMSO-d₆) δ ppm 0.62-0.71 (m, 2H) 0.93-1.02 (m, 2H) 1.37 (t, J=7.20 Hz,3H) 1.86-1.99 (m, 1H) 2.30 (s, 3H) 3.71 (s, 2H) 4.15 (q, J=7.24 Hz, 2H)6.16 (s, 1H) 6.71 (d, J=4.29 Hz, 1H) 6.87 (d, J=5.56 Hz, 1H) 7.12 (dd,J=9.09, 2.27 Hz, 1H) 7.46 (d, J=2.27 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H)8.31 (d, J=9.09 Hz, 1H) 8.61 (d, J=5.56 Hz, 1H) 10.64 (s, 1H).

EXAMPLE 151 Ba/F3-Tel-KDR Cell Viability Inhibition Assay

This assay is a cell-based assay to measure the compound-mediatedsuppression of Ba/F3 cell proliferation and viability using theLuciferase bioluminescent assay commercially known as CellTiter-Glo™. Inthis case, a specifically modified cell line, Ba/F3-Tel-KDR is used.These cells are engineered such that intact signaling through thetyrosine kinase domain of KDR is critical for their survival. Inhibitionof KDR signaling results in cell death which is quantitated using a cellviability assay. This is a homogeneous bioluminescent assay that yieldsa rapid, simple and sensitive determination of the number of viablecells in culture by generation of a luminescent signal proportional tothe amount of ATP present in cells. KDR inhibitor compound dilutions areincubated with Ba/F3-Tel-KDR cells over a 48 hour period and theresulting cell viability is measured with a suitable luminometer.

This assay is performed in Ba/F3-Tel-KDR cells. Cells are cultured at37° C. (5% CO₂) in medium containing RPMI-1640, 10% Fetal Bovine Serum,2 mM Glutamax, 100 units/ml Pen/Strep, and 0.8 mg/ml G418. Medium ischanged the day before the experiment. On Day 1, cells are plated intowhite solid bottom 384-well plates at 5000 cells/well in 25 μl culturemedium. A ten-point dose response curve is prepared as follows:compounds are first serially diluted 3-fold in 100% DMSO, starting from10 mM. Then the compounds are further diluted 166.67-fold in culturemedium. 5 μl of diluted compound is added to cell plates with 25 μlculture medium. The final concentrations of the compounds are: 10, 3.33,1.11, 0.37, 0.123, 0.041, 0.0137, 0.0046, 0.0015, and 0.0005 μM. Thefinal concentration of DMSO is 0.1%. Wells without or with cells plus0.1% DMSO serve as controls. On Day 3, Lyophilized CellTiter-Glo bufferand substrate and the cell plates are first equilibrated to roomtemperature. Substrate is reconstituted in buffer and 30 μlreconstituted substrate is added to each well. After incubation for 10minutes at room temperature, plates are read in a luminometer. Compoundsare tested in a 10-point dose response and each concentration is run intriplicate on a given plate. Each plate is run in duplicate. Dataanalysis and 1050 generation are performed using Excel and Prismsoftware.

Example Example number IC₅₀ (nM) number IC₅₀ (nM) 37-A 10 57-B 167 19-A76 102-A-1 2 33-D 189 102-A-2 12 27-A 5 19-AP 430 19-Y 23 54-Q 3 33-C 1059-C 114 86-A <1 56-F 8 76-E <1 56-G 2 35 13 54-O <1 57-A 4 73-D 9 64-A8 54-Q 7 45-B <1 42-E 81 56-B <1 98-B <1 52-B-1 58 87-E 7 52-B-2 78 74-A162 33-E 9 40 13 59-B 4 24-F 2 45-G 3 27-I <1 57-S 49 54-B 1 57-N 9154-C 19 57-T 6 39 2 51-C 1 24-F 24 63-A 8 51-D 11 33-H 330 33-L 87 96-A1 54-H 1 28-B 11 54-I <1 49-B 22 19-K 222 55-B 107 20-C 6 111-B 10 137-O10 136-B 2 136-J 36 135-E <1 56-S 89 134-A 3 135-BE <1 134-AG 95 134-AM6 57-AB <1 56-U 2 54-V 63 135-D <1 134-AC 4 137-E 9 135-C <1 137-F 19135-A 2 137-P 11 136-I 1 135-BI 3 136-K 91 57-C <1 137-C 3 25-D 3 149-F6 137-N 14 137-AA 2 135-AS 10 137-AB 1 148-G 88 135-AA <1 135-BH 2 137-I100 68-F 8

1-23. (canceled)
 24. A compound, or salt thereof, according to theformula:


25. A compound, or salt thereof, according to claim 24, which compoundis


26. A pharmaceutical composition comprising at least one compound ofclaim 24 and at least one pharmaceutically acceptable carrier.
 27. Apharmaceutical combination, comprising a therapeutically effectiveamount of the compound according to claim 24 and one or more additionaltherapeutically active agents.
 28. A method of inhibiting VEGF-Ractivity in a subject, wherein the method comprises administering to thesubject a therapeutically effective amount of the compound according toclaim
 24. 29. A method of treating a disorder or a disease in a subjectmediated by VEGF-R, wherein the method comprises administering to thesubject a therapeutically effective amount of the compound according toclaim 24 and the disease or disorder is selected from age relatedmacular degeneration, diabetic retinopathy, retinitis pigmentosa andretinopathy, geographic atrophy.
 30. A pharmaceutical compositioncomprising at least one compound of claim 25 and at least onepharmaceutically acceptable carrier.
 31. A pharmaceutical combination,comprising a therapeutically effective amount of the compound accordingto claim 25 and one or more additional therapeutically active agents.32. A method of inhibiting VEGF-R activity in a subject, wherein themethod comprises administering to the subject a therapeuticallyeffective amount of the compound according to claim
 25. 33. A method oftreating a disorder or a disease in a subject mediated by VEGF-R,wherein the method comprises administering to the subject atherapeutically effective amount of the compound according to claim 25and the disease or disorder is selected from age related maculardegeneration, diabetic retinopathy, retinitis pigmentosa andretinopathy, geographic atrophy.